Methods of treating mixed dyslipidemia

ABSTRACT

The present disclosure relates to, inter alia, methods of treating cardiovascular-related disease.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. patent application Ser. No.16/284,543 filed Feb. 25, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/725,617 filed on Oct. 5, 2017 (now allowed),which is a continuation of U.S. patent application Ser. No. 14/704,329filed on May 5, 2015 (now U.S. Pat. No. 9,855,237), which is acontinuation of U.S. patent application Ser. No. 14/175,602 filed Feb.7, 2014 (now U.S. Pat. No. 9,056,088), which is a continuation of U.S.patent application Ser. No. 13/898,447 filed on May 20, 2013 (now U.S.Pat. No. 8,691,871), which is a continuation of U.S. patent applicationSer. No. 13/540,319 filed on Jul. 2, 2012 (now U.S. Pat. No. 8,618,166),which is a continuation of U.S. patent application Ser. No. 13/417,899filed on Mar. 12, 2012 (now U.S. Pat. No. 8,563,608), which is acontinuation of U.S. patent application Ser. No. 13/266,085 filed onJan. 30, 2012, which is a National Stage Entry of International PatentApplication No. PCT/US10/32948 filed on Apr. 29, 2010, which claimspriority from U.S. Provisional Patent Application No. 61/173,759 filedon Apr. 29, 2009, the entirety of each of which are incorporated hereinby reference and relied upon.

BACKGROUND

Cardiovascular disease is one of the leading causes of death in theUnited States and most European countries. It is estimated that over 70million people in the United States alone suffer from a cardiovasculardisease or disorder including but not limited to high blood pressure,coronary heart disease, dyslipidemia, congestive heart failure andstroke.

SUMMARY

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising EPA and optionally one or more additionalcardiovascular agents. In another embodiment, the EPA compriseseicosapentaenoic acid ethyl ester. In another embodiment, thecomposition contains substantially no amount of docosahexaenoic acid orderivative thereof (e.g. ethyl-DHA), if any.

In other embodiments, the present invention provides methods of treatingand/or preventing a cardiovascular-related disease comprisingadministering to a subject in need thereof a pharmaceutical compositionor composition(s) comprising EPA and optionally one or more additionalcardiovascular agents.

In any of the foregoing embodiments, the EPA and additionalcardiovascular agent(s) can be co-formulated as a single dosage unit orcan be formulated as two to a plurality of dosage units for coordinated,combination or concomitant administration.

These and other embodiments of the present invention will be disclosedin further detail herein below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows effects of EPA, DHA and Combination Treatment on membranelipid peroxidation at cholesterol-to-phospholipid ratio of 1.0.

FIG. 2 shows effects of EPA, DHA and Combination Treatment on membranelipid peroxidation at cholesterol-to-phospholipid ratio of 0.5.

FIG. 3 shows cholesterol-dependent effects of EPA, DHA and CombinationTreatment on membrane lipid peroxidation.

FIG. 4 EPA, DHA or EPA/DHA with atorvastatin (10:1 Mole Ratio) on lipidperoxide levels in cholesterol enriched membranes (1:1cholesterol-to-phospholipid ratio).

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” In this manner,slight variations from a stated value can be used to achievesubstantially the same results as the stated value. Also, the disclosureof ranges is intended as a continuous range including every valuebetween the minimum and maximum values recited as well as any rangesthat can be formed by such values. Also disclosed herein are any and allratios (and ranges of any such ratios) that can be formed by dividing arecited numeric value into any other recited numeric value. Accordingly,the skilled person will appreciate that many such ratios, ranges, andranges of ratios can be unambiguously derived from the numerical valuespresented herein and in all instances such ratios, ranges, and ranges ofratios represent various embodiments of the present invention.

Eicosapentaenoic Acid

In one embodiment, compositions of the invention comprise EPA as anactive ingredient. The term “EPA” as used herein refers toeicosapentaenoic acid (e.g. eicosa-5,8,11,14,17-pentaenoic acid) and/ora pharmaceutically acceptable ester, derivative, conjugate or saltthereof, or mixtures of any of the foregoing. The term “pharmaceuticallyacceptable” in the present context means that the substance in questiondoes not produce unacceptable toxicity to the subject or interactionwith other components of the composition.

In one embodiment, the EPA comprises all-ciseicosa-5,8,11,14,17-pentaenoic acid. In another embodiment, the EPA isin the form of an eicosapentaenoic acid ester (also referred to hereinas E-EPA or ethyl-EPA). In another embodiment, the EPA comprises a C₁-C₅alkyl ester of EPA. In another embodiment, the EPA comprises,eicosapentaenoic acid methyl ester, eicosapentaenoic acid propyl ester,or eicosapentaenoic acid butyl ester. In still another embodiment, theEPA comprises all-cis eicosa-5,8,11,14,17-pentaenoic acid ethyl ester.

In another embodiment, the EPA comprises lithium EPA, mono, di- ortriglyceride EPA or any other ester or salt of EPA, or the free acidform of EPA. The EPA may also be in the form of a 2-substitutedderivative or other derivative which slows down its rate of oxidationbut does not otherwise change its biological action to any substantialdegree.

In one embodiment, EPA present in a composition of the inventioncomprises ultra-pure EPA. The term “ultra-pure” as used herein withrespect to EPA refers to a composition comprising at least 96% by weightEPA (as the term “EPA” is defined and exemplified herein). Ultra-pureEPA can comprise even higher purity EPA, for example at least 97% byweight EPA or at least 98% by weight EPA, wherein the EPA is any form ofEPA as set forth herein. Ultra-pure EPA can further be defined (e.g.impurity profile) by any of the description of EPA provided herein.

In another embodiment, the EPA comprises an EPA-Fatty Acid conjugatewherein EPA is conjugated to another molecule of EPA or to another fattyacid. In one embodiment, the EPA-Fatty Acid conjugate comprises adiester formed between EPA and EPA or between EPA a second fatty acid asshown in structures (I) and (II). In one embodiment, R¹ is a fatty acidacyl group derived from EPA and R² is selected from H, a fatty acid acylof 12 to 30 carbon atoms with two or more cis or trans double bonds andfatty alcohol groups of 12 to 30 carbon atoms, the same or differentthan R¹. R¹ and R² may both be derived from EPA (EPA-EPA) or one may bederived from EPA and the second from a different fatty acid (EPA-Fattyacid), for example gamma-linolenic acid, dihomo-gammalinolenic acid,arachidonic acid, adrenic acid, stearidonic acid, docosapentaenoic acidn-3, etc.). R³ is generally either hydrogen, fully hydrocarbon, orcontaining heteroatoms, and in one embodiment is a C₁-C₄ alkyl group.

Synthesis of a diester conjugate can be accomplished according tomethods well known in the art, including for example, using metals,metal-chlorides, or organic acids as catalysts; using fatty acidchlorides such as EPA-chloride, γ-linolenic acid chloride (GLAchloride),dihomo-γ-linolenic acid chloride (DGLA-chloride), linoleic acid chloride(LA-chloride), arachidonic acid chloride (AA-chloride), conjugatedlinoleic acid chloride (cLA-chloride), ALA-chloride, STA-chloride,ETA-chloride, DPA-chloride, etc.; and the use of immobilized enzymes ascatalysts.

In another embodiment, a composition of the present invention includes amixture of EPA-Fatty Acid diesters. In a related embodiment,compositions of the present invention include less than 20% EPA-DHAconjugate, less than 15% EPA-DHA conjugate, less than 10% EPA-DHAconjugate, less than 9% EPA-DHA conjugate, less than 8% EPADHAconjugate, less than 7% EPA-DHA conjugate, less than 6% EPA-DHAconjugate, less than 5% EPA-DHA conjugate, less than 4% EPA-DHAconjugate, less than 3% EPA-DHA conjugate, less than 2% EPA-DHAconjugate, less than 1% EPA-DHA conjugate, less than 0.5% EPA-DHAconjugate, or less than 0.1% EPA-DHA conjugate, by weight.

In another embodiment, a composition of the present invention includesat least 96% EPA-Fatty acid conjugate (e.g. EPA-EPA), at least 97%EPA-Fatty acid conjugate, at least 98% EPA-Fatty acid conjugate, or atleast 99% EPA-Fatty acid conjugate. In another embodiment, a compositionof the present invention contains no more than 10%, no more than 9%, nomore than 8%, no more than 7%, no more than 6%, no more than 5%, no morethan 4%, no more than 3%, no more than 2%, no more than 1%, or no morethan 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, nomore than 0.2, or no more than 0.1% of any EPA-Fatty Acid conjugateother than EPA-EPA diester.

In another embodiment, EPA is present in a composition of the inventionin an amount of about 50 mg to about 5000 mg, about 75 mg to about 2500mg, or about 100 mg to about 1000 mg, for example about 75 mg, about 100mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about1100 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg,about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg,about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg,about 1925 mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg,about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, or about2500 mg.

In one embodiment, a composition of the invention contains not more thanabout 10%, not more than about 9%, not more than about 8%, not more thanabout 7%, not more than about 6%, not more than about 5%, not more thanabout 4%, not more than about 3%, not more than about 2%, not more thanabout 1%, or not more than about 0.5%, by weight of total fatty acids,docosahexaenoic acid or derivative thereof such as ethyl-DHA (E-DHA), ifany. In another embodiment, a composition of the invention containssubstantially no docosahexaenoic acid or derivative thereof such asE-DHA. In still another embodiment, a composition of the inventioncontains no docosahexaenoic acid or E-DHA.

In another embodiment, EPA represents at least about 60%, at least about70%, at least about 80%, at least about 90%, at least about 95%, atleast about 97%, at least about 98%, at least about 99%, or 100%, byweight, of all fatty acids present in a composition of the invention.

In another embodiment, a composition of the invention contains less than30%, less than 20%, less than 10%, less than 9%, less than 8%, less than7%, less than 6%, less than 5%, less than 4%, less than 3%, less than2%, less than 1%, less than 0.5% or less than 0.25%, by weight of thetotal composition or by weight of the total fatty acid content, of anyfatty acid other than EPA, or derivative thereof. Illustrative examplesof a “fatty acid other than EPA” include linolenic acid (LA) orderivative thereof such as ethyl-linolenic acid, arachidonic acid (AA)or derivative thereof such as ethyl-AA, docosahexaenoic acid (DHA) orderivative thereof such as ethyl-DHA, alpha-linolenic acid (ALA) orderivative thereof such as ethyl-ALA, stearadonic acid (STA) orderivative thereof such as ethyl-SA, eicosatrienoic acid (ETA) orderivative thereof such as ethyl-ETA and/or docosapentaenoic acid (DPA)or derivative thereof such as ethyl-DPA.

In another embodiment, a composition of the invention has one or more ofthe following features: (a) eicosapentaenoic acid ethyl ester representsat least 96%, at least 97%, or at least 98%, by weight, of total fattyacids present in the composition; (b) the composition contains not morethan 4%, not more than 3%, or not more than 2%, by weight, of totalfatty acids other than eicosapentaenoic acid ethyl ester; (c) thecomposition contains not more than 0.6%, 0.5%, or 0.4% of any individualfatty acid other than eicosapentaenoic acid ethyl ester; (d) thecomposition has a refractive index (20° C.) of about 1 to about 2, about1.2 to about 1.8 or about 1.4 to about 1.5; (e) the composition has aspecific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 to about0.95 or about 0.9 to about 0.92; (f) the composition contains not morethan 20 ppm, 15 ppm or 10 ppm heavy metals, (g) the composition containsnot more than 5 ppm, 4 ppm, 3 ppm, or 2 ppm arsenic, and/or (h) thecomposition has a peroxide value not more than 5, 4, 3, or 2 Meq/kg.

In another embodiment, a composition useful in accordance with theinvention comprises, consists essentially of or consists of at least 95%ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% ethyloctadecatetraenoate (ODTA-E), about 0.05% to about 0.25% ethylnonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% ethylarachidonate (AA-E), about 0.3% to about 0.5% ethyl eicosatetraenoate(ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate(HPA-E), each by weight of total fatty acids present in the composition.In another embodiment, the composition is present in a capsule shell. Instill another embodiment, the capsule shell contains no chemicallymodified gelatin.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of, or consist of at least 95%,96% or 97%, ethyl eicosapentaenoate, about 0.2% to about 0.5% ethyloctadecatetraenoate, about 0.05% to about 0.25% ethylnonaecapentaenoate, about 0.2% to about 0.45% ethyl arachidonate, about0.3% to about 0.5% ethyl eicosatetraenoate, and about 0.05% to about0.32% ethyl heneicosapentaenoate, each by weight of all fatty acidspresent in the composition. Optionally, the composition contains notmore than about 0.06%, about 0.05%, or about 0.04%, by weight of totalfatty acids present, DHA or derivative thereof such as ethyl-DHA. In oneembodiment the composition contains substantially no or no amount of DHAor derivative thereof such as ethyl-DHA. The composition furtheroptionally comprises one or more antioxidants (e.g. tocopherol) in anamount of not more than about 0.5% or not more than 0.05%. In anotherembodiment, the composition comprises about 0.05% to about 0.4%, forexample about 0.2% by weight tocopherol. In another embodiment, about500 mg to about 1 g of the composition is provided in a capsule shell.In another embodiment, the capsule shell contains no chemically modifiedgelatin.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of, or consist of at least 96%ethyl eicosapentaenoate, about 0.22% to about 0.4% ethyloctadecatetraenoate, about 0.075% to about 0.20% ethylnonaecapentaenoate, about 0.25% to about 0.40% ethyl arachidonate, about0.3% to about 0.4% ethyl eicosatetraenoate and about 0.075% to about0.25% ethyl heneicosapentaenoate, each by weight of total fatty acidspresent in the composition. Optionally, the composition contains notmore than about 0.06%, about 0.05%, or about 0.04%, by weight of totalfatty acids present, DHA or derivative thereof such as ethyl-DHA. In oneembodiment the composition contains substantially no or no amount of DHAor derivative thereof such as ethyl-DHA. The composition furtheroptionally comprises one or more antioxidants (e.g. tocopherol) in anamount of not more than about 0.5% or not more than 0.05%. In anotherembodiment, the composition comprises about 0.05% to about 0.4%, forexample about 0.2% by weight tocopherol. In another embodiment, theinvention provides a dosage form comprising about 500 mg to about 1 g ofthe foregoing composition in a capsule shell. In one embodiment, thedosage form is a gel- or liquid-containing capsule and is packaged inblister packages of about 1 to about 20 capsules per sheet.

In another embodiment, compositions useful in accordance with theinvention comprise, consist essentially of or consist of at least 96%,97% or 98%, by weight, ethyl eicosapentaenoate, about 0.25% to about0.38% by weight ethyl octadecatetraenoate, about 0.10% to about 0.15% byweight ethyl nonaecapentaenoate, about 0.25% to about 0.35% by weightethyl arachidonate, about 0.31% to about 0.38% by weight ethyleicosatetraenoate, and about 0.08% to about 0.20% ethylheneicosapentaenoate, each by weight of all fatty acids present in thecomposition. Optionally, the composition contains not more than about0.06%, about 0.05%, or about 0.04%, by weight of all fatty acidspresent, DHA or derivative thereof such as ethyl-DHA. In one embodimentthe composition contains substantially no or no amount of DHA orderivative there of such as ethyl-DHA. The composition furtheroptionally comprises one or more antioxidants (e.g. tocopherol) in anamount of not more than about 0.5% or not more than 0.05%. In anotherembodiment, the composition comprises about 0.05% to about 0.4%, forexample about 0.2% by weight tocopherol. In another embodiment, theinvention provides a dosage form comprising about 500 mg to about 1 g ofthe foregoing composition in a capsule shell. In another embodiment, thecapsule shell contains no chemically modified gelatin.

Cardiovascular Agents

In one embodiment, a composition (or co-administration regimen) of theinvention comprises one or more additional cardiovascular agents. Theone or more additional cardiovascular agents can be co-formulated withEPA or can be co-administered with EPA. The interchangeable terms“cardiovascular agent” or “cardiovascular drug” herein refer to a drugor agent that is capable of treating, preventing, or reducing the riskof developing a cardiovascular disease or disorder, or a risk factor orsymptom thereof, in a subject. Cardiovascular agents herein can include,without limitation, cholesterol and triglyceride modulating agents,agents that treat coronary artery disease, agents that treathypertension or pulmonary arterial hypertension, agents that treatarterial fibrillation or arrhythmia, agents that treat stroke, agentsthat treat myocardial ischemia and/or agents that treat thrombosis.

Non-limiting examples of classes from which cardiovascular agentssuitable for use in accordance with the present invention can beselected include: Acyl-coenzyme A: cholesterol acyltransferase (ACAT)inhibitors including selective inhibitors of ACAT-1, ACAT-2 as well asdual inhibitors of ACAT-1 and ACAT-2, alpha-adrenergic blocking drugs(alpha-blockers), alpha/beta blockers, angiotensin-converting enzyme(ACE) inhibitors, aldosterone antagonists, angiotensin II receptorantagonists, anti-arrhythmics, anticoagulants, antiplatelet agents,apolipoprotein A-1 (apoA-1) mimetics, beta-blockers, bile acidsequestrants, calcium-channel blockers, ApoB cholesteryl ester transferprotein (CETP) inhibitors, cholesterol absorption inhibitors, diuretics,dyslipidemia agents, endothelin receptor antagonists, fibrates,3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors,LCAT activators, LDL receptor inducers, lipase inhibitors,lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors, microsomaltriglyceride transfer protein (MTP) inhibitors, platelet aggregationinhibitors, PPAR agonists and activators including PPARγ agonists, PPARαagonists and PPAR dual α/γ agonists, PCSK9 antisense or RNAi, squaleneepoxidase inhibitors, squalene synthetase inhibitors, thrombolytics, andthyroid receptor beta activators.

ACAT Inhibitors.

Acyl-CoA cholesteryl acyl transferase (“ACAT”) is an acyltransferaseenzyme. In bile acid biosynthesis, ACAT catalyzes the intracellularformation of cholesterol esters from cholesterol. ACAT promotesaccumulation of cholesterol esters in vascular tissues. Agents thatinhibit ACAT, therefore, are useful in preventing or treatingatherosclerosis. Non-limiting examples of suitable ACAT inhibitorsinclude CI-1011 (Avasimibe, Pfizer), CS-505 (Pactimibe sulfate, SankyoPharma), or combinations thereof.

One or more ACAT inhibitors, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about1000 mg, for example about 1 mg, about 5 mg, about 10 mg, about 20 mg,about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 266 mg, about 275mg, about 300 mg, about 324 mg, about 325 mg, about 330 mg, about 350mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975mg, about 1000 mg.

ACE Inhibitors.

Angiotensin I converting enzyme (“ACE”) converts angiontensin I toangiotensin II and inhibits bradykinin. Because increased angiotensin IIand decreased bradykinin levels both promote a variety of cardiovasculardiseases and disorders, agents that inhibit ACE are useful in preventingor treating cardiovascular-related diseases such as hypertension, heartfailure, diabetic neuropathy, and type 2 diabetes. Non-limiting examplesof suitable ACE inhibitors include captopril, enalapril, enaliprilat,trandolapril, moexipril, ramipril, quinapril, perindopril, lisinopril,benazepril, fosinopril, or combinations thereof.

One or more ACE inhibitors, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 0.5 mg toabout 50 mg, for example about 0.5 mg, about 0.75 mg, about 1 mg, about1.25 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg,about 6 mg, about 7 mg, about 7.5 mg, about 8 mg, about 9 mg, about 10mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg,about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg,about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg,about 49 mg, or about 50 mg.

Aldosterone Antagonists.

Aldosterone is a steroidal hormone that contributes to hypertension byinhibiting kidney function. Agents that compete with aldosterone formineralo-corticoid receptors are therefore useful in preventing ortreating hypertension. Non-limiting examples of suitable aldosteroneagents include eplerenone and aldactone, or combinations thereof.

Aldosterone antagonists, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 5 mg to about100 mg, for example about 5 mg, about 10 mg, about 12 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95, or about100 mg.

Alpha Blockers.

Alpha blockers, also called adrenergic alpha-antagonists, compete withadrenaline binding at α-adrenoreceptors. Adrenaline binding at suchreceptors leads to vasoconstriction and therefore hypertension. Agentsthat compete with adrenaline or block α-adrenoreceptors are thereforeuseful in preventing or treating hypertension. Non-limiting examples ofsuitable alpha blockers include doxazosin, methyldopa, clonidine,prazosin, terazosin, or combinations thereof.

Alpha blockers, if desired, are typically present in a composition ofthe invention (or co-administered with EPA according to otherembodiments of the invention) in an amount of about 0.02 mg to about 0.5mg, for example about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about0.1 mg, about 0.2 mg, about 2.5 mg, about 0.3 mg, about 3.5 mg, about0.4 mg, about 4.5 mg, or about 0.5 mg; in an amount of about 0.5 mg toabout 15 mg, for example about 0.5 mg, about 0.75 mg, about 1 mg, about2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg,about 14 mg, or about 15 mg; or in an amount of about 100 mg to about500 mg, for example about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, or about 500 mg.

Alpha/Beta Blockers.

One or more alpha/beta blockers, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about25 mg, for example about 1 mg, about 2 mg, about 3 mg, about 3.125 mg,about 4 mg, about 5 mg, about 6 mg, about 6.25 mg, about 7 mg, about 8mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg,about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24, orabout 25 mg. A non-limiting example of an alpha/beta blocker iscarvedilol.

Angiotensin II Receptor Antagonists.

Angiotensin II receptor antagonists, alternately called angiotensinreceptor blockers, ARBs, ATi-receptor antagonists, or sartans, areuseful in treating hypertension, congestive heart failure, and variousother diseases and disorders. Non-limiting examples of angiotensin IIreceptor antagonists include candesartan, irbesartan, olmesartan,losartan, valsartan, telmisartan, eprosartan, or combinations thereof.

One or more angiotensin II receptor antagonists, if desired, aretypically present in a composition of the invention (or co-administeredwith EPA according to other embodiments of the invention) in an amountof about 1 mg to about 100 mg, for example about 1 mg, about 2 mg, about3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about9 mg, about 10 mg, about 12 mg, about 15 mg, about 16 mg, about 20 mg,about 24 mg, about 25 mg, about 28 mg, about 30 mg, about 32 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about90 mg, about 95 mg, about 100 mg; in an amount of about 40 mg to about320 mg, for example, about 40 mg, about 60 mg, about 80 mg, about 100mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300mg, about 320 mg; in an amount of about 200 mg to about 800 mg, forexample about 200 mg, about 250 mg, about 300 mg, about 350 mg, about400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about650 mg, about 700 mg, about 750 mg, or about 800 mg.

Anti-Arrhythmic Agents.

Anti-arrhythmic drugs act to correct an irregular heartbeat and/or slowa heart that is beating too rapidly. Non-limiting examples of suitableanti-arrhythmic agents include adenosine, amiodarone, digoxin,disopyramide, flecainide, lidocaine, mexiletine, procainamide, quinidinegluconate, propafenone hydrochloride, tocainide, or combinationsthereof.

One or more anti-arrhythmics, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 0.1 mg toabout 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000mg, for example about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg,about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg,about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg,about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg,about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg,about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg,about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg,about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475mg, or about 1500 mg.

In an another embodiment, one or more anti-arrhythmics can be present inan amount of about 1 mg per mL to about 500 mg per mL, for example about1 mg per mL, about 2 mg per mL, about 3 mg per mL, about 4 mg per mL,about 5 mg per mL, about 6 mg per mL, about 10 mg per mL, about 25 mgper mL, about 50 mg per mL, about 75 mg per mL, about 80 mg per mL,about 100 mg per mL, about 125 mg per mL, about 150 mg per mL, about 175mg per mL, about 200 mg per mL, about 225 mg per mL, about 250 mg permL, about 275 mg per mL, about 300 mg per mL, about 325 mg per mL, about350 mg per mL, about 375 mg per mL, about 400 mg per mL, about 425 mgper mL, about 450 mg per mL, about 475 mg per mL, or about 500 mg permL.

In another embodiment, an anti-arrhythmics is present in an amount ofabout 0.01% to about 5%, for example about 0.01%, about 0.02%, about0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%,about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%,about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%,about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%,about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%,about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%,about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%,about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%,about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%,about 4.8%, about 4.9%, or about 5% by weight of the total composition.

Antiplatelet Agents.

Antiplatelet agents inhibit platelet aggregation and therefore combatthrombus development. Non-limiting examples of antiplatelet agentsinclude adeparin, aspirin, clopidogrel, danaparoid, deltaparin,denaparoid, ticlopidine, cilostazol, abciximab, eptifibatide, tirofiban,defibrotide, enoxaparin, dipyridamole, tinzaparin, or combinationsthereof.

One or more antiplatelet agents, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 10 mg to about100 mg, for example about 10 mg, about 12.5 mg, about 15 mg, about 20mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100mg; in an amount of about 50 mg to about 300 mg, for example about 50mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

In another embodiment, one or more antiplatelet agents are present in anamount of about 25 μg per mL to about 50 μg per mL, for example about 25μg per mL, about 30 μg per mL, about 35 μg per mL, about 40 μg per mL,about 45 μg per mL, or about 50 μg per mL; or in an amount of about 1 mgper mL to about 2 mg per mL, for example about 1 mg per mL, about 1.25mg per mL, about 1.50 mg per mL, about 1.75, or about 2 mg per mL.

Apoa-1 Mimetics.

Apolipoprotein A-1 (“apoA-1”) is the primary protein component of serumHDL cholesterol. Non-limiting examples of apoA-1 mimetics includeETC-216, ETC-588-liposome, ETC-642, trimeric apoA-1, CSL-111, APP018,reverse D-4F, or combinations thereof.

One or more apoA-1 mimetics, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 0.1 mg toabout 1500 mg, about 1 mg to about 1200 mg, or about 5 mg to about 1000mg, for example about 0.1 mg, about 0.5 mg, about 0.75 mg, about 1 mg,about 5 mg, about 6 mg, about 10 mg, about 20 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 266 mg, about 275 mg, about 300 mg,about 324 mg, about 325 mg, about 330 mg, about 350 mg, about 375 mg,about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg,about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg,about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg,about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg,about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg,about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025mg, about 1050 mg, about 1075 mg, or about 1200 mg, about 1225 mg, about1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg,about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475mg, or about 1500 mg.

Beta Blockers.

Beta blockers block responses to the beta nerve receptor which tends toslow heart rate and lower blood pressure. Non-limiting examples ofsuitable beta blockers include acebutolol, atenolol, metoprolol,nadolol, nebivolol, pindolol, propranolol, or combinations thereof.

One or more beta blockers, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about1000 mg, about 1 mg to about 750 mg, or about 1 mg to about 500 mg, forexample about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg,about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 120 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,about 450 mg, about 475 mg, or about 500 mg.

Bile Acid Sequestrants.

Bile acid sequestrants interrupt the enterohepatic circulation of bileacids by binding bile acid components in the gastrointestinal tract,rendering them unabsorbable thereafter. Bile acid sequestrants are thususeful in preventing or treating hyperlipidemia, among other diseasesand disorders. Non-limiting examples of bile acid sequestrants includecolesevelam Hcl, colestipol, locholest and cholestyramine orcombinations thereof.

One or more bile acid sequestrants, if desired, are typically present ina composition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 4 mg to about32 mg, for example about 4 mg, about 8 mg, about 12 mg, about 16 mg,about 24 mg, about 32 mg; or in an amount of about 300 mg to about 4000mg, for example about 300 mg, about 325 mg, about 350 mg, about 400 mg,about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 625 mg,about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg,about 1000 mg, about 1250 mg, about 1500 mg, about 1750 mg, about 2000mg, about 2250 mg, about 2500 mg, about 2750 mg, about 3000 mg, about3250 mg, about 3500 mg, about 3750, or about 4000 mg.

Calcium Channel Blockers.

Calcium channel blockers are useful in preventing or treatinghypertension by their vasodilating action. Non-limiting examples ofcalcium channel blockers include nicardipine, diltiazem, clevidipinebutyrate, isradipine, nimodipine, nisoldipine, verapamil, and amlodipinebesylate, or combinations thereof Non-limiting examples of combinationcalcium channel blockers include amlodipine, olmesartan, valsartan, orcombinations thereof.

One or more calcium channel blockers, if desired, are typically presentin a composition of the invention (or co-administered with EPA accordingto other embodiments of the invention) in an amount of about 1 mg toabout 10 mg, for example about 1 mg, about 2 mg, about 2.5 mg, about 3mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9mg, or about 10 mg; in an amount of about 5 mg to about 34 mg, forexample about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 8.5 mg,about 9 mg, about 10 mg, about 15 mg, about 17.5 mg, about 20 mg, about22.5 mg, about 25 mg, about 25.5 mg, about 27.5 mg, about 30 mg, about32.5, or about 34 mg; in an amount of about 10 mg to about 60 mg, forexample about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, orabout 60 mg; in an amount of about 20 mg to about 120 mg, for exampleabout 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about70 mg, about 80 mg, about 90 mg, about 100 mg, about 110, or about 120mg; in an amount of about 60 mg to about 420 mg, for example about 60mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg,about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg,about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg,about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400, orabout 420 mg.

In another embodiment, one or more calcium channel blockers is presentin an amount of about 0.05 mg per mL to about 2.5 mg per mL, for exampleabout 0.05 mg per mL, about 0.1 mg per mL, about 0.2 mg per mL, about0.3 mg per mL, about 0.4 mg per mL, about 0.5 mg per mL, about 0.6 mgper mL, about 0.7 mg per mL, about 0.8 mg per mL, about 0.9 mg per mL,about 1.0 mg per mL, about 1.25 mg per mL, about 1.5 mg per mL, about1.75 mg per mL, about 2.0 mg per mL, about 2.25 mg per mL, or about 2.5mg per mL.

CETP Inhibitors.

Cholesteryl ester transfer protein (“CETP”) plays an important role intransferring cholesteryl esters and triglycerides. Inhibition of CETP,also called plasma lipid transfer protein, is therefore useful inpreventing or treating atherosclerosis and other cardiovascular diseasesand disorders. Non-limiting examples of CETP inhibitors includetorcetrapib, anacetrapib, JTT-705, BAY-60-5521, PF-3185043, andCP-800569, or combinations thereof.

One or more CETP inhibitors, if desired, are present in a composition ofthe invention (or co-administered with EPA according to otherembodiments of the invention) in an amount sufficient to provide thesubject with a dose of about 25 mg per kg body weight (“mg per kg”) toabout 100 mg per kg, for example about 25 mg per kg, about 30 mg per kg,about 35 mg per kg, about 40 mg per kg, about 45 mg per kg, about 50 mgper kg, about 55 mg per kg, about 60 mg per kg, about 65 mg per kg,about 70 mg per kg, about 75 mg per kg, about 80 mg per kg, about 85 mgper kg, about 90 mg per kg, about 95 mg per kg, or about 100 mg per kg.

In another embodiment, one or more CETP inhibitors, if desired, arepresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about100 mg to about 10 g, about 500 mg to about 9 g, or about 750 mg toabout 5 g.

Cholesterol Absorption Inhibitors.

Cholesterol absorption inhibitors reduce the cholesterol content ofchylomicrons and chylomicron remnants by preventing the uptake ofmicellar cholesterol from the small intestine. As a result, lesscholesterol is delivered to the liver and thereby reduces LDL.Non-limiting examples of cholesterol absorption inhibitors includeezetimibe and simvastatin, or combinations thereof.

One or more cholesterol absorption inhibitors, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about 1mg to about 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, orabout 10 mg; or in an amount of about 10 to about 80 mg, for exampleabout 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, or about 80 mg.

Diuretics.

Diuretics increase urination rates forcing diuresis. Some diuretics alsoprovide antihypertensive effects. Non-limiting examples of diureticsinclude hydrochlorothiazide, torsemide, ethacrynic acid, furosemide,triamterene, indapamide, chlorothiazide sodium, aliskiren, orcombinations thereof.

One or more diuretics, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of: (a) about 0.25 mgto about 2.5 mg, for example about 0.25 mg, about 0.5 mg, about 0.75 mg,about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg,about 2.25 mg, or about 2.5 mg; (b) in an amount of about 5 mg to about25 mg, for example about 5 mg, about 10 mg, about 12.5 mg, about 15 mg,about 17.5 mg, about 20 mg, about 22.5 mg, or about 25 mg; (c) in anamount of about 2 mg to about 100 mg, for example about 2 mg, about 3mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 12.5 mg,about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about90 mg, about 95 mg, or about 100 mg; (d) about 10 mg to about 50 mg, forexample about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20mg, about 22.5 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, or about 50 mg; in an amount of about 5 mg to about 60 mg,for example about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, (e) or about 60 mg; in an amount of about 25 mg to about100 mg, for example about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about90 mg, or about 100 mg; in an amount of about 75 mg to about 300 mg, forexample about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300mg; (f) about 0.1 g to about 0.5 g, for example about 0.1 g, about 0.2g, about 0.3 g, about 0.4 g, or about 0.5 g; or (g) in an amount ofabout 1 mg per mL to about 10 mg per mL, for example about 1 mg per mL,about 2 mg per mL, about 3 mg per mL, about 4 mg per mL, about 5 mg permL, about 6 mg per mL, about 7 mg per mL, about 8 mg per mL, about 9 mgper mL, or about 10 mg per mL.

Dyslipidemia Agents.

Dyslipidemia is a class of diseases that includes hyperlipidemia.Fredrickson's Type I dyslipidemia (sometimes referred to asBuerger-Gruetz syndrome, primary hyperlipoproteinaemia, or familialhyperchylomicronemia) is characterized by elevated cholesterol levels,subjects with Fredrickson's Type Ila dyslipidemia (also known asfamilial hypercholesterolemia) exhibit elevated LDL levels. Those withFredrickson's Type IIb dyslipidemia (familial combinedhyperlipoproteinemia (FCH) or secondary combined hyperlipoproteinemia)show increased LDL and VLDL levels. Fredrickson's Type III dyslipidemia(sometimes called beta disease or dysbetalipoproteinemia) featureselevated intermediate density lipoproteins (“IDL”), while Fredrickson'sType IV dyslipidemics (sometimes called “pure hypertriglyceridemics”)have elevated VLDL levels. Subjects with Fredrickson's Type Vdyslipidemia have increased VLDL and chylomicron levels.

Non-limiting examples of dyslipidemia agents include Angptl4 antibody,APA-01 (Phosphagenics), CRD-5 (ImaSight), NCX6560 (NicOx), PCSK9 RNAi(Alnylam), recombinant apoA-1 (SemBioSys Genetics), anti-oxLDL(Genentech), APL180 (Novartis), APP018 (D4F) (Novartis), CER-002(Cerenis Therapeutics), CP-800,569 (Pfizer), GSK256073(GlaxoSmithKline), MB07811 (Metabasis), PF-3, 185,043 (Pfizer), R7232(Roche), rilapladib (GlaxoSmithKline), RVX-208 (Resverlogix), Sobetirome(QRX-431 (QuatRx)), anacetrapib (Merk), CSL111 (CSL Limited), darapladib(GlaxoSmithKline), eprotirome (Karo Bio), GFT505 (Genfit), MAHDLO1(Marzal Plant Pharma), MBX-8025 (Metabolex), PLX204 (Wyeth/Plexxikon),aleglitezar (Roche), dalcetrapib (Roche), SLx4090 (Surface Logix),verespladib (Anthera Pharmaceuticals), AEGR-733 (Aegerion), ABT-335(Abbott Laboratories), AVE5530 (Sanofi-Aventis), LCP-AtorFen (LifeCyclePharma), TRIA-662 (Cortria), fenofibrate, choline fenofibrate,ezetimibe, colsevelam, laropiprant, or combinations of any of theforegoing.

One or more dyslipidemia agents, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg,about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 43 mg, about 45 mg, about 48 mg, about 50 mg, about 54 mg,about 55 mg, about 60 mg, about 65 mg, about 67 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 87 mg, about 90 mg, about 95 mg,about 100 mg, about 105 mg, about 107 mg, about 110 mg, about 115 mg,about 120 mg, about 125 mg, about 130 mg, about 134 mg, about 135 mg,about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg,about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 275 mg,about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 575 mg,about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg,about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg,about 975 mg, or about 1000 mg.

Endothelin Receptor Antagonists.

Binding of endothelin-1 at endothelin-A (ETA) or endothelin-B (ETB)receptors causes pulmonary vasoconstriction. Endothelin receptorantagonists compete with endothelin-1 binding, thereby attenuatingpulmonary vasoconstriction. Endothelin receptor antagonists, therefore,are useful in treating pulmonary hypertension. Non-limiting examples ofendothelin receptor antagonists include ambrisentan, bosentan, volibris,thelin, or combinations thereof.

One or more endothelin receptor antagonists, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about 1mg to about 10 mg, for example about 1 mg, about 2 mg, about 3 mg, about4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, orabout 10 mg; in an amount of about 50 mg to about 250 mg, for exampleabout 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg,about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

HMG-CoA Reductase Inhibitors.

HMG-CoA reductase (also known as HMGR) converts HMG-CoA(3-hydroxy-3-methyl-glutaryl-coenzyme A) to mevalonic acid(3,5-dihydroxy-3-methyl-pentanoic acid) along the metabolic pathway thatproduces cholesterol. HMG-CoA reductase inhibitors, also called statins,inhibit HMG-CoA reductase and thereby reduce cholesterol production. Asa result, HMG-CoA reductase inhibitors are useful in treating a varietyof cardiovascular diseases and disorders including, for example,hypercholesterolemia, hyperlipidemia, mixed dyslipidemia,hypertriglyceridemia, atherosclerosis, Non-limiting examples of HMG-CoAreductase inhibitors include lovastatin, lovastatin+niacin, mevastatin,pitavastatin, pravastatin, rosuvastatin, fluvastatin, atorvastatin,atorvastatin+amlodipine besylate, simvastatin, simvistatin+niacin,ezetimibe, and pravastatin, among others.

One or more HMG-CoA reductase inhibitors, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about 1mg to about 1000 mg, for example about 1 mg, about 2 mg, about 3 mg,about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg,or about 10 mg; about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg,about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg,about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg,about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg,about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg,about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg,about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg,about 975 mg, or about 1000 mg.

LCAT Activators.

Lecithin-cholesterol acyltransferase (“LCAT”) converts cholesterol intocholesteryl ester. In subjects with deficient levels of LCAT,unesterified cholesterol accumulates in body tissues. This can lead toelevated serum levels of HDL and eventually atherosclerosis. LCATactivators are therefore useful in reducing serum HDL levels andtreating or preventing atherosclerosis. Non-limiting examples of LCATactivators include LCAT enzyme, recombinant LCAT, genetic therapy agentsthat include a nucleic acid sequence coding for expression of LCAT,estrogens, estrogen analogs, and combinations thereof for example asdisclosed in U.S. Pat. No. 6,635,614 incorporated by reference herein inits entirety.

One or more LCAT activators, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount sufficient to raise theserum LCAT level of the subject to a desired level. Subjects withabnormally low LCAT serum levels may be administered an amount of acomposition of the invention comprising EPA and LCAT enzyme, estrogen,estrogen analogs, or combinations thereof sufficient to raise thesubject's serum LCAT level to normal levels, typically about 5 μg per mLor greater. In another embodiment, subjects with about normal LCAT serumlevels may be treated with a composition of the invention comprising EPAand LCAT enzyme, estrogen, estrogen analogs, or combinations thereof inan amount sufficient to raise the LCAT serum level to about 6 μg per mLor more, about 7 μg per mL or more, about 8 μg per mL or more, about 9μg per mL or more, or about 10 μg per mL or more.

LDL Receptor Inducers.

LDL receptors are cell surface proteins. Along with adaptin, LDLreceptors bind free LDL cholesterol to form clathrin-coated vesicles,reducing serum LDL levels. Thus, agents that induce LDL receptorsfurther reduce serum LDL levels and are useful in preventing or treatingatherosclerosis. A non-limiting example of LDL receptor is lactacystin.

One or more LDL receptor inducers, if desired, are typically present ina composition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg,about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10mg about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg,about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg,about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg,about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg,about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg,about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg,about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, orabout 1000 mg.

Lp-PLA2 Inhibitors.

Compositions of the invention may comprise one or more lipoproteinassociated phospholipase A2 (Lp-PLA2) inhibitors. Lp-PLA2 hydrolyzesoxidized phospholipids in LDL cholesterols. High levels of Lp-PLA2 seemto trigger a cascade of inflammatory events in atherosclerosis and anincreased risk of stroke. Lp-PLA2 inhibitors, therefore, are useful inslowing or preventing development of atherosclerosis. Non-limitingexamples of Lp-PLA2 inhibitors include rilapladib, darapladib, andcombinations thereof.

One or more Lp-PLA2 inhibitors, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 1 mg to about1000 mg, for example about 1 mg, about 2 mg, about 3 mg, about 4 mg,about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10mg; about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg,about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg,about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg,about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg,about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg,about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg,about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg,about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, orabout 1000 mg.

5-Lipoxygenase Inhibitors.

5-lipoxygenase inhibitors are useful in accordance with variousembodiments of the invention. Non-limiting examples of 5-lipixygenaseinhibitors include VIA-2291, MK-886, CMI 977, ABT-761, ZD2138,lonapalene, zileuton, 5-LO inhibitor 6, L-739,010, CGS 22745, SC 45662,and combinations thereof

Additional 5-lipoxygenase inhibitors suitable for use in accordance withembodiments of the instant invention are disclosed in the following U.S.patents and patent applications, each of which is hereby incorporated byreference herein in its entirety: U.S. 20050101659, U.S. Pat. Nos.7,026,344, 7,329,682, U.S. 20040198768, U.S. 20090054519, U.S. Pat. Nos.5,112,848, 5,086,052, U.S. 482828, U.S. Pat. Nos. 5,208,364, 4,970,210,4,794,114, 4,686,231, 5,134,150, 5,639,782, 6,239,170, U.S. 20060106014,U.S. Pat. Nos. 5,229,386, 4,673,684, 6,136,839, 6,090,547, 6,355,434,U.S. 20090042849, U.S. Pat. Nos. 4,731,382, 4,877,881, 5,130,485,5,665,752, 5,723,481, 5,102,897, 5,234,939, 5,143,928, 5,217,971,4,889,941, 5,234,937, 5,283,361, 5,232,939, 5,086,064, 5,208,251,5,290,800, 5,006,549, 5,494,927, U.S. 20040198800, U.S. Pat. Nos.4,719,218, 4,847,270, 6,121,323, U.S. 20080226758, U.S. 20070218146,U.S. Pat. Nos. 4,728,656, 4,835,189, 5,763,673, 4,835,190, 5,162,365,5,985,937, 6,455,541, 5,534,524, U.S. 20070134341, U.S. 20050267145,U.S. Pat. Nos. 4,694,018, 5,260,294, 5,792,776, 5,530,141, 5,780,503,5,093,356, 5,348,957, 5,384,318, U.S. 568822, U.S. 20010009918, U.S.20070219206, U.S. 20070225285, U.S. 20050267211, U.S. 20030162193, U.S.20070173508, U.S. 20070066577, U.S. Pat. No. 5,036,067, U.S.20030082108, U.S. 20090018170, U.S. 20070105866, U.S. 20070237848, U.S.20070244185, U.S. 20080227807, U.S. Pat. Nos. 4,728,735, 4,803,279,4,962,119, 5,314,898, U.S. 20070123522, U.S. 20070123522, U.S.20070244128, U.S. 20070093524, U.S. Pat. Nos. 4,602,023, 4,943,587,6,025,384, U.S. 20090118373, U.S. Pat. Nos. 5,112,868, 5,254,553,5,312,821, 5,635,514, 7,405,302, 4,624,964, 4,786,755, 4,933,351,5,059,609, 5,442,111, 5,066,668, 5,292,900, 5,998,451, 4,851,586,5,314,900, 5,447,943, 6,221,880, 6,262,077, 6,376,528, 6,569,895,4,663,347, 4,975,457, 4,978,679, 5,703,093, 5,811,432, 4,822,803,5,356,921, 5,750,565, 4,751,310, 4,816,486, 5,288,751, 5,298,512,5,909,734, 4,745,127, 5,215,986, 5,270,319, 5,476,944, 4,939,169,6,166,031, 6,696,477, 6,756,399, 4,931,444, 5,066,658, 5,248,685,5,240,929, 4,861,798, 4,933,329, 5,008,390, 5,814,648, 6,939,674,5,696,141, 5,434,151, U.S. 20030216481, U.S. 20030232763, U.S.20060177528, U.S. 20030235620, U.S. 20020177723, U.S. Pat. Nos.5,036,105, 5,504,097, 5,741,809, 5,459,154, 5,463,083, 6,420,392,5,358,938, 5,326,907, 6,294,574, 5,648,486, 5,856,323, 7,387,797,4,801,611, 5,530,114, 7,514,469, U.S. 20010025040, U.S. 20020143033,U.S. Pat. No. 5,665,749, U.S. 20010009917, U.S. 20070049621, U.S.20080280826, U.S. Pat. Nos. 5,393,923, 5,114,958, 5,376,670, 6,217,875,5,155,122, 5,288,896, 6,436,924, 5,256,680, 7,132,441, 5,145,860,5,354,768, 5,698,576, 7,371,874, 5,068,251, 5,130,483, 6,177,415,5,541,218, U.S. 20070264361, U.S. Pat. Nos. 5,284,949, 4,672,075,5,212,189, 5,302,597, U.S. 20080107757, U.S. Pat. Nos. 6,620,813,5,250,565, U.S. 624012, U.S. Pat. Nos. 4,732,901, 5,196,431, 5,340,815,5,504,108, 5,220,025, 5,252,562, 5,420,131, 5,037,837, 5,081,126,5,105,020, 5,187,175, 5,342,838, 4,755,525, 5,248,682, 4,963,576,5,514,703, 6,194,585, 6,194,585, 6,291,534, 4,695,586, 4,971,979,6,653,311, 4,755,524, 5,147,893, 4,711,903, U.S. 20040077691, U.S. Pat.No. 4,695,585, U.S. 2005009084, U.S. Pat. Nos. 5,516,789, 5,512,594,U.S. 20070202206, U.S. Pat. Nos. 6,261,607, 5,350,754, 6,344,563, U.S.20040235807, U.S. Pat. Nos. 5,064,851, 5,254,581, 5,288,742, 5,403,859,5,407,945, U.S. 20030008914, U.S. Pat. Nos. 5,254,731, 5,318,970,5,519,022, 6,174,883, 6,262,073, U.S. 20040170974, U.S. 20070231345,U.S. Pat. Nos. 4,985,435, 5,126,365, 5,234,950, 5,321,025, 5,484,805,5,221,677, 5,280,047, 5,300,655, and 5,359,063.

One or more 5-lipoxygenase inhibitors, if desired, are typically presentin a composition of the invention (or co-administered with EPA accordingto other embodiments of the invention) in an amount of about 0.01 mg toabout 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg to about 1200mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5,about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg,about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg,about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg,about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg,about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg,about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg,about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg,about 2475 mg or about 2500 mg.

Microsomal Triglyceride Transfer Protein Inhibitors.

Microsomal triglyceride transfer protein (“MTTP” or “MTP”) is aheterodimeric protein involved in lipoprotein assembly. MTP inhibitorsare thus useful in slowing or preventing the production of lipoproteinsand therefore cardiovascular diseases and disorders. Non-limitingexamples of MTP inhibitors include SLx-4090, AEGR-733, implitapide,BMS-200150, CP-346086, JTT-130, dirlotapide, and combinations thereof.

Additional MTP inhibitors suitable for use in accordance withembodiments of the instant invention are disclosed in the following U.S.patents and patent applications, each of which is hereby incorporated byreference herein in its entirety: U.S. 20030166590, U.S. Pat. No.6,492,365, U.S. 20040132779, U.S. 20040132745, U.S. 20050181376, U.S.20030086912, U.S. Pat. No. 6,767,739, U.S. 20080249130, U.S.20020028943, U.S. Pat. Nos. 5,883,099, 5,739,135, 5,712,279, 6,034,098,5,827,875, 6,066,650, 5,885,983, U.S. 20060166999, U.S. 20070027183,U.S. 20020045271, U.S. Pat. No. 6,288,234, U.S. 20030109700, U.S.20040014748, 6878707, 6218524, 5595872, U.S. 20080253985, U.S.20080103122, U.S. 20050234073, U.S. 20050090426, U.S. 20040044008, U.S.20090042835, U.S. 20040058908, U.S. 20060270655, U.S. Pat. No.6,369,075, U.S. 20080241869, U.S. 20070093468, U.S. 20090054393, U.S.20020132806, U.S. 20070088089, U.S. 20040033506, U.S. 20080161279, U.S.20020161233, U.S. 20020042516, U.S. 20070093527, U.S. Pat. No.6,713,489, U.S. 20060211020, U.S. Pat. Nos. 6,617,325, 6,147,214 andU.S. 20020032238.

In one embodiment, one or more MTP inhibitors, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount sufficientto provide the subject with a dose of about 1 μg per kg of body weight(μg per kg) to about 100 μg per kg, for example about 25 μg per kg,about 30 μg per kg, about 35 μg per kg, about 40 μg per kg, about 45 μgper kg, about 50 μg per kg, about 55 μg per kg, about 60 μg per kg,about 65 μg per kg, about 70 μg per kg, about 75 μg per kg, about 80 μgper kg, about 85 μg per kg, about 90 μg per kg, about 95 μg per kg, orabout 100 μg per kg. In another embodiment, one or more MTP inhibitors,if desired, are present in a composition of the invention (orco-administered with EPA according to other embodiments of theinvention) in an amount of about 30 μg to about 20 mg, about 50 μg toabout 15 mg, or about 70 μg to about 10 mg.

In another embodiment, one or more MTP inhibitors, if desired, arepresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about0.01 mg to about 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg toabout 1200 mg, or about 5 mg to about 1000 mg, for example about 0.1 mg,about 0.5, about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg,about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg,about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg,about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg,about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg,about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg,about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg,about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg,about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050mg, about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg,about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg,about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg,about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg,about 2450 mg, about 2475 mg or about 2500 mg.

PPAR Agonists and Activators.

Peroxisome proliferator-activated receptors (“PPARs”) are nuclearreceptor proteins regulating the expression of genes by acting astranscription factors in combination with the retinoid X receptor(“RXR”). Agents that inhibit or activate PPARs are therefore useful inmodifying the expression of certain genes including, for example, genesassociated with metabolic disorders such as hypercholesterolemia.Non-limiting examples of PPAR agonists and activators includefenofibrate, bezafibrate, ciprofibrate, clofibrate, gemfibrozil,CER-002, rosiglitazone, GW501516, RWJ 800025, KD-3010, and combinationsthereof

One or more PPAR agonists and/or activators, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about0.5 mg to about 4 mg, for example about 0.5 mg, about 0.75 mg, about 1mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5mg, about 3.75 mg, or about 4 mg; or in an amount of about 20 mg toabout 120 mg, for example about 20 mg, about 30 mg, about 40 mg, about50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,about 110 mg, or about 120 mg.

sPLA2 Inhibitors.

sPLA2 inhibitors are suitable for use in accordance with variousembodiments of the present invention. Non-limiting examples of sPLA2inhibitors include LY 333013, varespladib, WA8242A, WA8242A2, WA8242B,A-0001, A-0002 and combinations thereof.

Additional sPLA2 inhibitors suitable for use in accordance withembodiments of the instant invention are disclosed in the following U.S.patents and patent applications, each of which is hereby incorporated byreference herein in its entirety: U.S. Pat. Nos. 6,974,831, 6,916,840,6,992,100, 6,872,743, U.S.20040063967, U.S.20040063941, U.S.20040092543,U.S.20040077704, U.S. Pat. No. 6,433,001, U.S.20030153770,U.S.20030191175, U.S. Pat. Nos. 6,706,752, 6,730,694, U.S.20040059130,U.S. Pat. Nos. 7,026,348, 6,608,099, 6,340,699, 6,252,084, 6,635,670,6,939,890, 6,930,123, 6,713,505, 6,274,578, 6,451,839, U.S.20040029948,U.S.20090062369, U.S.20030236232, U.S. Pat. Nos. 7,160,909, 6,384,041,6,175,021, 6,214,876, U.S.20090131396, U.S. Pat. Nos. 6,353,128,6,407,104, 6,274,616, U.S.20030087944, U.S. Pat. No. 5,916,922,U.S.20040198801, U.S.20080249027, U.S. Pat. Nos. 7,026,318, 6,933,313,U.S.20040087796, U.S. Pat. No. 6,391,908, U.S.20030181454, U.S. Pat.Nos. 6,831,095, 6,177,426, U.S.20060116379, U.S. Pat. Nos. 6,472,389,6,797,708, U.S.20090118503, U.S.20070249008, U.S. Pat. Nos. 7,087,637,5,919,810, 6,828,344, 6,916,841, 5,654,326, 5,641,800, 5,733,923,6,534,535, U.S.20050026988, U.S. Pat. Nos. 6,166,062, 5,684,034,7,253,194, U.S.20080045444, U.S.20040033995, U.S.20060235009,U.S.20090088427, U.S. Pat. No. 7,196,103, U.S.20080317809,U.S.20090092595, U.S.20070037253, U.S. Pat. Nos. 7,098,237, 6,140,327,5,972,972, U.S.20040248898, U.S. Pat. No. 6,967,200, U.S.20030092767,U.S.20040106669, U.S.20040077651, U.S.20050158401, U.S. Pat. No.6,514,984, U.S.20040102442, U.S. Pat. No. 6,610,728, U.S.20030119860,U.S. Pat. Nos. 6,436,983, 6,703,385, 6,576,654, 7,101,875, 6,635,771,6,756,376, 6,984,735, 6,448,284, 6,787,545, 6,265,591, 6,713,645,6,673,781, 6,214,855, 6,008,231, 6,344,467, 6,177,440, 6,426,344,7,105,514, 6,214,991, U.S.20020169108, U.S.20060025348, U.S.20030008816,U.S.20090029917, U.S. Pat. Nos. 6,900,208, 6,380,397, 7,205,329,5,919,943, 7,126,010, 7,109,231, 6,555,568, 6,872,557, 7,030,112,7,041,695, 7,220,756, 7,396,838, 6,407,261, 6,028,116, 5,965,619,6,063,818, 5,998,477, 6,121,321, 6,958,348, 7,528,112, 6,903,104,6,745,133, 6,861,436, 5,650,374, 6,569,539, 6,432,987, 5,762,413,7,176,281, 7,317,009, 7,153,854, U.S.20020110523, U.S. Pat. Nos.6,776,986, 5,948,779, 7,449,615, 7,531,568, 7,476,746, 7,491,831,6,231,189, 6,987,105, 7,300,932, 6,962,784, 6,248,553, 6,255,063,U.S.20070053912, U.S. Pat. No. 6,974,831, U.S.20040063941,U.S.20040077704, U.S.20040248898, U.S.20040063967, U.S. Pat. No.6,992,100, U.S.20040092543, U.S. Pat. Nos. 6,916,840, 6,433,001,U.S.20070249008, U.S.20090092595, U.S. Pat. No. 6,872,743,U.S.20070037253.

One or more sPLA2 inhibitors, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 0.01 mg toabout 2500 mg, about 0.1 mg to about 1500 mg, about 1 mg to about 1200mg, or about 5 mg to about 1000 mg, for example about 0.1 mg, about 0.5,about 0.75 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg,about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg,about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg,about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg,about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg,about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg,about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about 1075mg, or about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg,about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg,about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, about2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg,about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg,about 2475 mg or about 2500 mg.

Squalene Epoxidase Inhibitors.

Squalene epoxidase, also called squalene monooxygenase, catalyzes theoxidation of squalene in the cholesterol biosynthesis pathway. Thus,agents that inhibit squalene epoxidase are useful in preventing orslowing the cholesterol production. Non-limiting examples of squaleneepoxidase inhibitors include terbinafine, naftifine, amorolfine,butenafine, FR194738, NB-598, resveratrol(trans-3,4′,5-trihydroxystilbene), epigallocatechin-3-O-gallate,S-allylcysteine, selenocysteine, alliin, diallyl trisulfide, diallyldisulfide, and combinations thereof.

One or more squalene epoxidase inhibitors, if desired, are typicallypresent in a composition of the invention (or co-administered with EPAaccording to other embodiments of the invention) in an amount of about100 mg to 250 mg, for example about 100 mg, about 125 mg, about 150 mg,about 175 mg, about 200 mg, about 225 mg, or about 250 mg; or in anamount of about 0.5% to about 5%, by weight of the composition, forexample about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%,about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%,about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%,about 4.75%, or about 5%, by weight.

Thrombolytic Agents.

Thrombolytic agents dissolve blood clots. Thrombolytic agents aretherefore useful in treating cardiovascular diseases and disordersincluding, for example, deep vein thrombosis, pulmonary embolism,ischemic complications, unstable angina, myocardial infarction, andvenous thromboembolism, among others. Non-limiting examples ofthrombolytic agents include fondoparinux, dalteparin, enoxaparin,apixaban, PD-348292, and combinations thereof.

One or more thrombolytic agents, if desired, are typically present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount sufficient to provide adosage of about 0.5 mg per kg of body weight (“mg per kg”) to about 40mg per kg, for example about 0.5 mg per kg, about 1 mg per kg, about 2mg per kg, about 3 mg per kg, about 4 mg per kg, about 5 mg per kg,about 6 mg per kg, about 7 mg per kg, about 8 mg per kg, about 9 mg perkg, about 10 mg per kg, about 11 mg per kg, about 12 mg per kg, about 13mg per kg, about 14 mg per kg, about 15 mg per kg, about 16 mg per kg,about 17 mg per kg, about 18 mg per kg, about 19 mg per kg, about 20 mgper kg, about 21 mg per kg, about 22 mg per kg, about 23 mg per kg,about 24 mg per kg, about 25 mg per kg, about 26 mg per kg, about 27 mgper kg, about 28 mg per kg, about 29 mg per kg, about 30 mg per kg,about 31 mg per kg, about 32 mg per kg, about 33 mg per kg, about 34 mgper kg, about 35 mg per kg, about 36 mg per kg, about 37 mg per kg,about 38 mg per kg, about 39 mg per kg, or about 40 mg per kg, or in atotal amount of about 30 mg to about 3.5 g.

In another embodiment, one or more thrombolytic agents are present in acomposition of the invention (or co-administered with EPA according toother embodiments of the invention) in an amount of about 0.5 mg toabout 2.5 mg, for example 0.5 mg, about 0.75 mg, about 1 mg, about 1.25mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, or about 2.5mg; or in an amount sufficient to provide about 60 international unitsper kg of body weight (“IU per kg”) to about 240 IU per kg, for example60 IU per kg, about 70 IU per kg, about 80 IU per kg, about 90 IU perkg, about 100 IU per kg, about 110 IU per kg, about 120 IU per kg, about130 IU per kg, about 140 IU per kg, about 150 IU per kg, about 160 IUper kg, about 170 IU per kg, about 180 IU per kg, about 190 IU per kg,about 200 IU per kg, about 210 IU per kg, about 220 IU per kg, about 230IU per kg, or about 240 IU per kg.

Other Cardiovascular Agents.

Other cardiovascular agents are also useful in preventing, inhibiting,or treating cardiovascular diseases or disorders. Non-limiting examplesof other cardiovascular agents include gemfibrozil, niaspan, orlistat,GFT14, AZD-2479, ETC-1001, and combinations thereof.

One or more of these other cardiovascular agents, if desired, can bepresent in a composition of the invention (or may be co-administeredwith EPA according to other embodiments of the invention) in an amountcorresponding to the recommended or suggested dosage for the particularcardiovascular agent(s). In a related embodiment, the cardiovascularagent(s) may be present in a composition of the invention (or may beco-administered with EPA according to other embodiments of theinvention) in an amount less than the recommended or suggested dosagefor the particular cardiovascular agent(s). For example, a compositionof the invention may comprise EPA and one or more of these othercardiovascular agents in an amount of about 5 mg to about 1500 mg forexample about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about250 mg, about 266 mg, about 275 mg, about 300 mg, about 324 mg, about325 mg, about 330 mg, about 350 mg, about 375 mg, about 400 mg, about425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg,about 1075 mg, or about 1200 mg, about 1225 mg, about 1250 mg, about1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg,about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, or about1500 mg.

Headings used to describe cardiovascular agents herein are not to beconstrued as limiting in any manner. Many cardiovascular agents can havemultiple modes of action and can be described under one or moreheadings.

Salts and Other Derivatives

Salts, hydrates, solvate, esters, amides, enantiomers, isomers,tautomers, polymorphs, prodrugs, and derivatives of any of the foregoingdrugs may be used in accordance with the invention and may be preparedusing standard procedures known to those skilled in the art of syntheticorganic chemistry. See, e.g., March, Advanced Organic Chemistry:Reactions, Mechanisms and Structure, 4th Ed. (New York:Wiley-lnterscience, 1992); Leonard et al., Advanced Practical OrganicChemistry (1992); Howarth et al., Core Organic Chemistry (1998); andWeisermel et al., Industrial Organic Chemistry (2002).

“Pharmaceutically acceptable salts,” or “salts,” include the salt of adrug prepared from formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic,methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, beta-hydroxybutyric, galactaric andgalacturonic acids.

In one embodiment, acid addition salts are prepared from the free baseforms using conventional methodology involving reaction of the free basewith a suitable acid. Suitable acids for preparing acid addition saltsinclude both organic acids, e.g., acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like.

In another embodiment, base addition salts are prepared from the freeacid forms using conventional methodology involving reaction of the freeacid with a suitable base.

In other embodiments, an acid addition salt is reconverted to the freebase by treatment with a suitable base. In a further embodiment, theacid addition salts are halide salts, which are prepared usinghydrochloric or hydrobromic acids. In still other embodiments, the basicsalts are alkali metal salts, e.g., sodium salt. In other embodiments, abase addition salt is reconverted to the free acid by treatment with asuitable acid.

In one embodiment, EPA and one or more cardiovascular agent(s) arepresent in a composition of the invention, or are co-administered in aweight ratio of EPA:cardiovascular agent of about 1:1000 to about1000:1, about 1:500 to about 500:1, about 1:100 to about 100:1, about1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1,about 1:5 to about 5:1, about 1:4 to about 4:1 about 1:3 to about 3:1,about 1:2 to about 2:1 or about 1:1.

Antiretroviral Therapy

In one embodiment, the present invention provides a method of treating acardiovascular-related disease as defined herein, for exampledyslipidemia or hyperlipidemia, in an HIV positive subject. In anotherembodiment, the method comprises co-administration, or concomitantadministration, of a composition or compositions as disclosed hereinwith one or more HIV-1 protease inhibitors. Non-limiting examples ofHIV-1 protease inhibitors include amprenavir, fosamprenavir, indinavir,lopinavir, nelfinavir, ritonavir and saquinavir.

One or more HIV-1 protease inhibitors, if desired, are typically presentin a composition of the invention (or co-administered with EPA accordingto other embodiments of the invention) in an amount of about 100 mg toabout 2500 mg, for example about 125 mg, about 150 mg, about 175 mg,about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg,about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg,about 625 mg, about 650 mg, about 700 mg, about 800 mg, about 900 mg,about 1000 mg, about 1100 mg, about 1200 mg, about 1250 mg, about 1300mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about1800 mg, about 1825 mg, about 1900 mg, about 2000 mg, about 2100 mg,about 2200 mg, about 2300 mg, about 2400 mg, or about 2500 mg; in anamount of about 200 mg to about 1000 mg, for example about 200 mg, about300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about800 mg, about 900 mg, or about 1000 mg; in an amount of about 50 mg toabout 400 mg, for example about 50 mg, about 100 mg, about 150 mg, about200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg; in anamount of about 200 mg to about 1066 mg, for example about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about500 mg, about 533 mg, about 550 mg, about 600 mg, about 650 mg, about700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about950 mg, about 1000 mg, or about 1066 mg; in an amount of about 50 mg toabout 1200 mg, for example about 50 mg, about 100 mg, about 150 mg,about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg,about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg,about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg,about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150mg, or about 1200 mg; or in an amount of about 15 mg per kg body weightto about 40 mg per kg body weight, for example about 15 mg per kg, about20 mg per kg, about 25 mg per kg, about 30 mg per kg, about 35 mg perkg, about mg per kg, or about 40 mg per kg.

Dosage Forms

In one embodiment, compositions of the invention are orally deliverable.The terms “orally deliverable” or “oral administration” herein includeany form of delivery of a therapeutic agent or a composition thereof toa subject wherein the agent or composition is placed in the mouth of thesubject, whether or not the agent or composition is swallowed. Thus“oral administration” includes buccal and sublingual as well asesophageal administration.

In some embodiments, compositions of the invention are in the form ofsolid dosage forms. Non-limiting examples of suitable solid dosage formsinclude tablets (e.g. suspension tablets, bite suspension tablets, rapiddispersion tablets, chewable tablets, melt tablets, effervescenttablets, bilayer tablets, etc), caplets, capsules (e.g. a soft or a hardgelatin capsule filled with solid and/or liquids), powder (e.g. apackaged powder, a dispensable powder or an effervescent powder),lozenges, sachets, cachets, troches, pellets, granules, microgranules,encapsulated microgranules, powder aerosol formulations, or any othersolid dosage form reasonably adapted for oral administration.

EPA and/or any other desired cardiovascular agent(s) can beco-formulated in the same dosage unit, or can be individually formulatedin separate dosage units. The terms “dose unit” and “dosage unit” hereinrefer to a portion of a pharmaceutical composition that contains anamount of a therapeutic agent suitable for a single administration toprovide a therapeutic effect. Such dosage units may be administered oneto a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) oftimes per day, or as many times as needed to elicit a therapeuticresponse.

In one embodiment, a composition of the invention comprises one or morecardiovascular agents dispersed or suspended in EPA, wherein thedispersion or suspension is present in a capsule (for example gelatin orHPMC capsule), sachet, or other dosage form or carrier as describedherein. In another embodiment, the dispersion or suspension issubstantially uniform. In still another embodiment, whereco-administration of two or more dosage units is desired, the EPA ispresent in a first dosage unit, for example a suspension in a capsule,and the cardiovascular agent is present in second dosage unit, forexample a tablet. Optionally, any desired additional cardiovascularagent can be present in a third composition.

In another embodiment, composition(s) of the invention can be in theform of liquid dosage forms or dose units to be imbibed directly or theycan be mixed with food or beverage prior to ingestion. Non-limitingexamples of suitable liquid dosage forms include solutions, suspension,elixirs, syrups, liquid aerosol formulations, etc.

In one embodiment, compositions of the invention, upon storage in aclosed container maintained at room temperature, refrigerated (e.g.about 5 to about 5-10° C.) temperature, or frozen for a period of about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about90%, at least about 95%, at least about 97.5%, or at least about 99% ofthe active ingredient(s) originally present therein.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising EPA and a cardiovascular agent (fill)encapsulated in a capsule shell, wherein the fill has a baselineperoxide value not greater than about 10 Meq/kg, about 9 Meq/kg, about 8Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5 Meq/kg, about 4 Meq/kg,about 3 Meq/kg or about 2 Meq/kg, wherein upon storage of thecomposition at 23° C. and 50% RH for a period about 1, about 2, about 3,about 4, about 5, about 6, about 7, about 8, about 9, about 10, about11, about 12, about 13, about 14, about 15, about 16, about 17, about18, about 19, about 20, about 21, about 22, about 23 or about 24 months,the ultra-pure EPA has a second peroxide value not greater than about 25Meq/kg, about 24 Meq/kg, about 23 Meq/kg, about 22 Meq/kg, about 21Meq/kg, about 20 Meq/kg, about 19 Meq/kg, about 18 Meq/kg, about 17Meq/kg, about 16 Meq/kg, about 15 Meq/kg, about 14 Meq/kg, about 13Meq/kg, about 12 Meq/kg, about 11 Meq/kg, about 10 Meq/kg, about 9Meq/kg, about 8 Meq/kg, about 7 Meq/kg, about 6 Meq/kg, about 5 Meq/kg,about 4 Meq/kg, about 3 Meq/kg or about 2 Meq/kg.

Upon storage, some pharmaceutical compositions degrade over time.Degradation products can alter a composition's efficacy, for example bydelivering less active ingredient to a subject than recommended.Degradation products for new drugs above certain thresholds should bereported to the Food & Drug Administration (FDA) in accordance withcurrent Guidance Documents. Degradation products above a certainthreshold amount should be identified. A degradation product is“identified” when its structural characterization has been achieved.Degradation products above a certain amount should be qualified. Adegradation product is “qualified” when its biological safety isacquired and evaluated.

In one embodiment, compositions of the invention with a maximum dailydose of less than or equal to 1 gram, upon storage under light, heat,humidity, acid/base hydrolytic, and/or oxidative conditions, containless than about 0.1% of any degradation product not reported to the Foodand Drug Administration (FDA). In another embodiment, compositions ofthe invention with a maximum daily dose of greater than 1 gram, uponstorage under light, heat, humidity, acid/base hydrolytic, and/oroxidative conditions, contain less than about 0.05% of any degradationproduct not reported to the FDA.

In one embodiment, compositions of the invention with a maximum dailydose of less than 1 mg, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 1% of any unidentified degradation product. In another embodiment,compositions of the invention with a maximum daily dose of less than 1mg, upon storage under light, heat, humidity, acid/base hydrolytic,and/or oxidative conditions, contain less than about 5 μg of anyunidentified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of 1 mg to 10 mg, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.5% of any unidentified degradation product. In anotherembodiment, compositions of the invention with a maximum daily dose of 1mg to 10 mg, upon storage under light, heat, humidity, acid/basehydrolytic, and/or oxidative conditions, contain less than about 20 μgof any unidentified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of 10 mg to 2 g, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.2% of any unidentified degradation product. In anotherembodiment, compositions of the invention with a maximum daily dose of10 mg to 2 g, upon storage under light, heat, humidity, acid/basehydrolytic, and/or oxidative conditions, contain less than about 2 mg ofany unidentified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of greater than 2 g, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.1% of any unidentified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of less than 10 mg, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 1% of any unqualified degradation product. In another embodiment,compositions of the invention with a maximum daily dose of less than 10mg, upon storage under light, heat, humidity, acid/base hydrolytic,and/or oxidative conditions, contain less than about 50 μg of anyunqualified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of 10 mg to 100 mg, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.5% of any unqualified degradation product. In anotherembodiment, compositions of the invention with a maximum daily dose of10 mg to 100 mg, upon storage under light, heat, humidity, acid/basehydrolytic, and/or oxidative conditions, contain less than about 200 μgof any unqualified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of 100 mg to 2 g, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.2% of any unqualified degradation product. In anotherembodiment, compositions of the invention with a maximum daily dose of100 mg to 2 g, upon storage under light, heat, humidity, acid/basehydrolytic, and/or oxidative conditions, contain less than about 3 mg ofany unqualified degradation product.

In one embodiment, compositions of the invention with a maximum dailydose of greater than 2 g, upon storage under light, heat, humidity,acid/base hydrolytic, and/or oxidative conditions, contain less thanabout 0.15% of any unqualified degradation product.

In some embodiments, compositions of the invention comprise astabilizing agent that suppresses, prevents, hinders, or otherwiseattenuates the decomposition of the active ingredient(s) during storage.For example, oxidative decomposition of EPA in compositions of theinvention may be prevented or attenuated by the presence ofantioxidants. Non-limiting examples of suitable antioxidants includetocopherol, lecithin, citric acid and/or ascorbic acid. One or moreantioxidants, if desired, are typically present in a composition in anamount of about 0.01% to about 0.1%, by weight, or about 0.025% to about0.05%, by weight.

Excipients

Compositions of the invention optionally comprise one or morepharmaceutically acceptable excipients. The term “pharmaceuticallyacceptable excipient” herein means any substance, not itself atherapeutic agent, used as a carrier or vehicle for delivery of atherapeutic agent to a subject or added to a pharmaceutical compositionto improve its handling or storage properties or to permit or facilitateformation of a unit dose of the composition, and that does not produceunacceptable toxicity or interaction with other components in thecomposition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable diluents as excipients. Suitable diluentsillustratively include, either individually or in combination, lactose,including anhydrous lactose and lactose monohydrate; starches, includingdirectly compressible starch and hydrolyzed starches (e.g., Celutab™ andEmdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000)and dextrose monohydrate; dibasic calcium phosphate dihydrate;sucrose-based diluents; confectioners sugar; monobasic calcium sulfatemonohydrate; calcium sulfate dihydrate; granular calcium lactatetrihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;celluloses including microcrystalline cellulose, food grade sources ofa- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose;calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and thelike. Such diluents, if present, constitute in total about 5% to about99%, about 10% to about 85%, or about 20% to about 80%, of the totalweight of the composition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable disintegrants as excipients. Suitabledisintegrants include, either individually or in combination, starches,including sodium starch glycolate (e.g., Explotab™ of PenWest) andpregelatinized corn starches (e.g., National™ 1551, National™ 1550, andColocorn™ 1500), clays (e.g., Veegum™ HV), celluloses such as purifiedcellulose, microcrystalline cellulose, methylcellulose,carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellosesodium (e.g., Ac-Di-Sol™ of FMC), alginates, crospovidone, and gums suchas agar, guar, xanthan, locust bean, karaya, pectin and tragacanth gums.Such disintegrants, if present, typically comprise in total about 0.2%to about 30%, about 0.2% to about 10%, or about 0.2% to about 5%, of thetotal weight of the composition.

Compositions of the invention optionally comprise one or moreantioxidants. Illustrative antioxidants include sodium ascorbate andvitamin E (tocopherol). One or more antioxidants, if present, aretypically present in a composition of the invention in an amount ofabout 0.001% to about 5%, about 0.005% to about 2.5%, or about 0.01% toabout 1%, by weight.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable binding agents or adhesives as excipients.Such binding agents and adhesives can impart sufficient cohesion to apowder being tableted to allow for normal processing operations such assizing, lubrication, compression and packaging, but still allow thetablet to disintegrate and the composition to be absorbed uponingestion. Suitable binding agents and adhesives include, eitherindividually or in combination, acacia; tragacanth; sucrose; gelatin;glucose; starches such as, but not limited to, pregelatinized starches(e.g., National™ 1511 and National™ 1500); celluloses such as, but notlimited to, methylcellulose and carmellose sodium (e.g., Tylose™);alginic acid and salts of alginic acid; magnesium aluminum silicate;PEG; guar gum; polysaccharide acids; bentonites; povidone, for examplepovidone K-15, K-30 and K-29/32; polymethacrylates; HPMC;hydroxypropylcellulose (e.g., Klucel™); and ethylcellulose (e.g.,Ethocel™). Such binding agents and/or adhesives, if present, constitutein total about 0.5% to about 25%, about 0.75% to about 15%, or about 1%to about 10%, of the total weight of the composition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable wetting agents as excipients. Non-limitingexamples of surfactants that can be used as wetting agents incompositions of the invention include quaternary ammonium compounds, forexample benzalkonium chloride, benzethonium chloride and cetylpyridiniumchloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenylethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9,poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefossé), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereofSuch wetting agents, if present, constitute in total about 0.25% toabout 15%, about 0.4% to about 10%, or about 0.5% to about 5%, of thetotal weight of the composition.

Compositions of the invention optionally comprise one or morepharmaceutically acceptable lubricants (including anti-adherents and/orglidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behapate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium (magnesiumstearate), calcium and sodium stearates; hydrogenated vegetable oils(e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodiumbenzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine;PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodiumlauryl sulfate; and magnesium lauryl sulfate. Such lubricants, ifpresent, constitute in total about 0.1% to about 10%, about 0.2% toabout 8%, or about 0.25% to about 5%, of the total weight of thecomposition.

Suitable anti-adherents include talc, cornstarch, DL-leucine, sodiumlauryl sulfate and metallic stearates. Talc is an anti-adherent orglidant used, for example, to reduce formulation sticking to equipmentsurfaces and also to reduce static in the blend. Talc, if present,constitutes about 0.1% to about 10%, about 0.25% to about 5%, or about0.5% to about 2%, of the total weight of the composition. Glidants canbe used to promote powder flow of a solid formulation. Suitable glidantsinclude colloidal silicon dioxide, starch, talc, tribasic calciumphosphate, powdered cellulose and magnesium trisilicate.

Compositions of the present invention optionally comprise one or moreflavoring agents, sweetening agents, and/or colorants. Flavoring agentsuseful in the present invention include, without limitation, acaciasyrup, alitame, anise, apple, aspartame, banana, Bavarian cream, berry,black currant, butter, butter pecan, butterscotch, calcium citrate,camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus,citrus punch, citrus cream, cocoa, coffee, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,MagnaSweet®, maltol, mannitol, maple, menthol, mint, mint cream, mixedberry, nut, orange, peanut butter, pear, peppermint, peppermint cream,Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole,sorbitol, spearmint, spearmint cream, strawberry, strawberry cream,stevia, sucralose, sucrose, Swiss cream, tagatose, tangerine, thaumatin,tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen,xylitol, and combinations thereof, for example, anise-menthol,cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream,vanilla-mint, etc.

Sweetening agents that can be used in the present invention include, forexample, acesulfame potassium (acesulfame K), alitame, aspartame,cyclamate, cylamate, dextrose, isomalt, MagnaSweet®, maltitol, mannitol,neohesperidine DC, neotame, Prosweet® Powder, saccharin, sorbitol,stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.

Flavoring agents, sweetening agents, and/or colorants can be present incompositions of the invention in any suitable amount, for example about0.01% to about 10%, about 0.1% to about 8%, or about 1% to about 5%, byweight.

Compositions of the invention optionally comprise a suspending agent.Non-limiting illustrative examples of suitable suspending agents includesilicon dioxide, bentonite, hydrated aluminum silicate (e.g. kaolin) andmixtures thereof One or more suspending agents are optionally present incompositions of the invention in a total amount of about 0.01% to about3.0%, about 0.1% to about 2.0%, or about 0.25% to about 1.0%, by weight.

The foregoing excipients can have multiple roles as is known in the art.For example, starch can serve as a filler as well as a disintegrant. Theclassification of excipients above is not to be construed as limiting inany manner. Excipients categorized in any manner may also operate undervarious different categories of excipients as will be readilyappreciated by one of ordinary skill in the art.

Therapeutic Methods

In various embodiments, compositions of the invention are useful fortreatment and/or prevention of a cardiovascular-related disease. Theterm “cardiovascular-related disease” herein refers to any disease ordisorder of the heart or blood vessels (i.e. arteries and veins) or anysymptom thereof, or any disease or condition that causes or contributesto a cardiovascular disease.” Non-limiting examples ofcardiovascular-related diseases and disorders include acute cardiacischemic events, acute myocardial infarction, angina, angina pectoris,arrhythmia, atrial fibrulation, atherosclerosis, arterial fibrillation,cardiac insufficiency, cardiovascular disease, chronic heart failure,chronic stable angina, congestive heart failure, coronary arterydisease, coronary heart disease, deep vein thrombosis, diabetes,diabetes mellitus, diabetic neuropathy, diastolic dysfunction insubjects with diabetes mellitus, edema, essential hypertension, eventualpulmonary embolism, fatty liver disease, heart disease, heart failure,homozygous familial hypercholesterolemia (HoFH), homozygous familialsitosterolemia, hypercholesterolemia, hyperlipidemia, hyperlipidemia inHIV positive subjects, hypertension, hypertriglyceridemia, ischemiccomplications in unstable angina and myocardial infarction, low bloodpressure, metabolic syndrome, mixed dyslipidemia, moderate to mild heartfailure, myocardial infarction, obesity management, paroxysmalatrial/arterial fibrillation/fibrulation/flutter, paroxysmalsupraventricular tachycardias (PSVT), particularly severe or rapid onsetedema, platelet aggregation, primary hypercholesterolemia, primaryhyperlipidemia, pulmonary arterial hypertension, pulmonary hypertension,recurrent hemodynamically unstable ventricular tachycardia (VT),recurrent ventricular arrhythmias, recurrent ventricular fibrillation(VF), ruptured aneurysm, sitisterolemia, stroke, supraventriculartachycardia, symptomatic atrial fibrillation/flutter, tachycardia,type-II diabetes, vascular disease, venous thromboembolism, ventriculararrhythmias, and other cardiovascular events.

The term “treatment” in relation a given disease or disorder, includes,but is not limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder, relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

In some embodiments, compositions of the present invention can beco-administered or administered concomitantly with one or moreadditional cardiovascular agents. The terms “co-administered,”“concomitant administration,” and “administered concomitantly” are usedinterchangeably herein and each refer to, for example, administration oftwo or more agents (e.g., EPA or a derivative thereof and acardiovascular agent) at the same time, in the same dosage unit, oneimmediately after the other, within five minutes of each other, withinten minutes of each other, within fifteen minutes of each other, withinthirty minutes of each other, within one hour of each other, within twohours of each other, within four hours of each other, within six hoursof each other, within twelve hours of each other, within one day of eachother, within one week of each other, within two weeks of each other,within one month of each other, within two months of each other, withinsix months of each other, within one year of each other, etc.

In one embodiment, the present invention provides a method of treating acardiovascular-related disease comprising administering to a subject inneed thereof a composition or compositions comprising EPA and one ormore additional cardiovascular agents (either as a single dosage unit oras multiple dosage units), wherein one or more lipid parameters areimproved by comparison with lipid parameters achieved by the additiveeffects of the individual treatments.

In a related embodiment, upon treatment in accordance with the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits one or more of the following outcomes:

-   -   a) reduced triglyceride levels compared to baseline or a placebo        arm;    -   b) reduced Apo B levels compared to baseline or a placebo arm;    -   c) increased HDL-C levels compared to baseline or a placebo arm;    -   d) no increase in LDL-C levels compared to baseline or a placebo        arm;    -   e) a reduction in LDL-C levels compared to baseline or a placebo        arm;    -   f) a reduction in non-HDL-C levels compared to baseline or a        placebo arm;    -   g) a reduction in vLDL levels compared to baseline or a placebo        arm;    -   h) an increase in apo A-I levels compared to baseline or a        placebo arm;    -   i) an increase in apo A-I/apo B ratio compared to baseline or a        placebo arm;    -   j) a reduction in lipoprotein A levels compared to baseline or a        placebo arm;    -   k) an increase in LDL particle number compared to baseline or a        placebo arm;    -   l) a reduction in LDL size compared to baseline or a placebo        arm;    -   m) a reduction in remnant-like particle cholesterol compared to        baseline or a placebo arm;    -   n) a reduction in oxidized LDL compared to baseline or a placebo        arm;    -   o) no change or a reduction in fasting plasma glucose (FPG)        compared to baseline or a placebo arm;    -   p) a reduction in hemoglobin A_(1c) (HbA_(1c)) compared to        baseline or a placebo arm;    -   q) a reduction in homeostasis model insulin resistance compared        to baseline or a placebo arm;    -   r) a reduction in lipoprotein associated phospholipase A2        compared to baseline or a placebo arm;    -   s) a reduction in intracellular adhesion molecule-1 compared to        baseline or a placebo arm;    -   t) a reduction in interleukin-6 compared to baseline or a        placebo arm;    -   u) a reduction in plasminogen activator inhibitor-1 compared to        baseline or a placebo arm;    -   v) a reduction in high sensitivity C-reactive protein (hsCRP)        compared to baseline or a placebo arm;    -   w) an increase in serum phospholipid EPA compared to baseline or        a placebo arm;    -   x) an increase in red blood cell membrane EPA compared to        baseline or a placebo arm; and/or    -   y) a reduction or increase in one or more of serum phospholipid        and/or red blood cell content of docosahexaenoic acid (DHA),        docosapentaenoic acid (DPA), arachidonic acid (AA), palmitic        acid (PA), staeridonic acid (SA) or oleic acid (OA) compared to        baseline or a placebo arm.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(y) above priorto dosing the subject or subject group. In another embodiment, themethods comprise administering a composition as disclosed herein to thesubject after baseline levels of one or more markers set forth in(a)-(y) are determined, and subsequently taking an additionalmeasurement of said one or more markers.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more, any 24 or more, or all 25 of outcomes (a)-(y) describedimmediately above.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks,about 1 to about 2 weeks or about 1 week, the subject or subject groupexhibits one or more of the following outcomes:

-   -   a) a reduction in triglyceride level of at least about 5%, at        least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, at        least about 55% or at least about 75% (actual % change or median        % change) as compared to baseline or a placebo arm;    -   b) a less than 30% increase, less than 20% increase, less than        10% increase, less than 5% increase or no increase in non-HDL-C        levels or a reduction in non-HDLC levels of at least about 1%,        at least about 3%, at least about 5%, at least about 10%, at        least about 15%, at least about 20%, at least about 25%, at        least about 30%, at least about 35%, at least about 40%, at        least about 45%, at least about 50%, at least about 55% or at        least about 75% (actual % change or median % change) as compared        to baseline or a placebo arm;    -   c) substantially no change, no change or an increase in HDL-C        levels of at least about 5%, at least about 10%, at least about        15%, at least about 20%, at least about 25%, at least about 30%,        at least about 35%, at least about 40%, at least about 45%, at        least about 50%, at least about 55% or at least about 75%        (actual % change or median % change) as compared to baseline or        a placebo arm;    -   d) a less than 60% increase, less than 50% increase, less than        40% increase, less than 30% increase, less than 20% increase,        less than 15% increase or no increase in LDL-C levels or a        reduction in LDL-C levels of at least about 5%, at least about        10%, at least about 15%, at least about 20%, at least about 25%,        at least about 30%, at least about 35%, at least about 40%, at        least about 45%, at least about 50%, at least about 55%, at        least about 55% or at least about 75% (actual % change or median        % change) as compared to baseline or a placebo arm;    -   e) a decrease in Apo B levels of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, at least about 50%, at least        about 55% or at least about 75% (actual % change or median %        change) as compared to baseline or a placebo arm;    -   f) a reduction in vLDL levels of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, at least about 50%, or at least        about 100% (actual % change or median % change) compared to        baseline or a placebo arm;    -   g) an increase in apo A-I levels of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, at least about 50%, or at least        about 100% (actual % change or median % change) compared to        baseline or a placebo arm;    -   h) an increase in apo A-I/apo B ratio of at least about 5%, at        least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, or at        least about 100% (actual % change or median % change) compared        to baseline or a placebo arm;    -   i) a reduction in lipoprotein(a) levels of at least about 5%, at        least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, or at        least about 100% (actual % change or median % change) compared        to baseline or a placebo arm;    -   j) a reduction in mean LDL particle number of at least about 5%,        at least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, or at        least about 100% (actual % change or median % change) compared        to baseline or a placebo arm;    -   k) an increase in mean LDL particle size of at least about 5%,        at least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, or at        least about 100% (actual % change or median % change) compared        to baseline or a placebo arm;    -   l) a reduction in remnant-like particle cholesterol of at least        about 5%, at least about 10%, at least about 15%, at least about        20%, at least about 25%, at least about 30%, at least about 35%,        at least about 40%, at least about 45%, at least about 50%, or        at least about 100% (actual % change or median % change)        compared to baseline or a placebo arm;    -   m) a reduction in oxidized LDL of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, at least about 50%, or at least        about 100% (actual % change or median % change) compared to        baseline or a placebo arm;    -   n) substantially no change, no change or a reduction in fasting        plasma glucose (FPG) of at least about 5%, at least about 10%,        at least about 15%, at least about 20%, at least about 25%, at        least about 30%, at least about 35%, at least about 40%, at        least about 45%, at least about 50%, or at least about 100%        (actual % change or median % change) compared to baseline or a        placebo arm;    -   o) substantially no change, no change or a reduction in        hemoglobin A_(1c) (HbA_(1c)) of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, or at least about 50% (actual %        change or median % change) compared to baseline or a placebo        arm;    -   p) a reduction in homeostasis model index insulin resistance of        at least about 5%, at least about 10%, at least about 15%, at        least about 20%, at least about 25%, at least about 30%, at        least about 35%, at least about 40%, at least about 45%, at        least about 50%, or at least about 100% (actual % change or        median % change) compared to baseline or a placebo arm;    -   q) a reduction in lipoprotein associated phospholipase A2 of at        least about 5%, at least about 10%, at least about 15%, at least        about 20%, at least about 25%, at least about 30%, at least        about 35%, at least about 40%, at least about 45%, at least        about 50%, or at least about 100% (actual % change or median %        change) compared to baseline or a placebo arm;    -   r) a reduction in intracellular adhesion molecule-1 of at least        about 5%, at least about 10%, at least about 15%, at least about        20%, at least about 25%, at least about 30%, at least about 35%,        at least about 40%, at least about 45%, at least about 50%, or        at least about 100% (actual % change or median % change)        compared to baseline or a placebo arm;    -   s) a reduction in interleukin-6 of at least about 5%, at least        about 10%, at least about 15%, at least about 20%, at least        about 25%, at least about 30%, at least about 35%, at least        about 40%, at least about 45%, at least about 50%, or at least        about 100% (actual % change or median % change) compared to        baseline or a placebo arm;    -   t) a reduction in plasminogen activator inhibitor-1 of at least        about 5%, at least about 10%, at least about 15%, at least about        20%, at least about 25%, at least about 30%, at least about 35%,        at least about 40%, at least about 45%, at least about 50%, or        at least about 100% (actual % change or median % change)        compared to baseline or a placebo arm;    -   u) a reduction in high sensitivity C-reactive protein (hsCRP) of        at least about 5%, at least about 10%, at least about 15%, at        least about 20%, at least about 25%, at least about 30%, at        least about 35%, at least about 40%, at least about 45%, at        least about 50%, or at least about 100% (actual % change or        median % change) compared to baseline or a placebo arm;    -   v) an increase in serum plasma and/or RBC EPA of at least about        5%, at least about 10%, at least about 15%, at least about 20%,        at least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, at        least about 100%, at least about 200% or at least about 400%        (actual % change or median % change) compared to baseline or a        placebo arm;    -   w) an increase in serum phospholipid and/or red blood cell        membrane EPA of at least about 5%, at least about 10%, at least        about 15%, at least about 20%, at least about 25%, at least        about 30%, at least about 35%, at least about 40%, at least        about 45%, r at least about 50%, at least about 100%, at least        about 200%, or at least about 400% (actual % change or median %        change) compared to baseline or a placebo arm;    -   x) a reduction or increase in one or more of serum phospholipid        and/or red blood cell DHA, DPA, AA, PA and/or OA of at least        about 5%, at least about 10%, at least about 15%, at least about        20%, at least about 25%, at least about 30%, at least about 35%,        at least about 40%, at least about 45%, at least about 50%, at        least about 55% or at least about 75% (actual % change or median        % change) compared to baseline or a placebo arm; and/or    -   y) (y) a reduction in total cholesterol of at least about 5%, at        least about 10%, at least about 15%, at least about 20%, at        least about 25%, at least about 30%, at least about 35%, at        least about 40%, at least about 45%, at least about 50%, at        least about 55% or at least about 75% (actual % change or median        % change) compared to baseline or a placebo arm.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(y) prior todosing the subject or subject group. In another embodiment, the methodscomprise administering a composition as disclosed herein to the subjectafter baseline levels of one or more markers set forth in (a)-(y) aredetermined, and subsequently taking a second measurement of the one ormore markers as measured at baseline for comparison thereto.

In another embodiment, upon treatment with a composition of the presentinvention, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, thesubject or subject group exhibits any 2 or more of, any 3 or more of,any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of,any 8 or more of, any 9 or more of, any 10 or more of, any 11 or moreof, any 12 or more of, any 13 or more of, any 14 or more of, any 15 ormore of, any 16 or more of, any 17 or more of, any 18 or more of, any 19or more of, any 20 or more of, any 21 or more of, any 22 or more of, any23 or more of, any 24 or more of, or all 25 of outcomes (a)-(y)described immediately above.

Parameters (a)-(y) can be measured in accordance with any clinicallyacceptable methodology. For example, triglycerides, total cholesterol,HDL-C and fasting blood sugar can be sample from serum and analyzedusing standard photometry techniques. VLDL-TG, LDL-C and VLDL-C can becalculated or determined using serum lipoprotein fractionation bypreparative ultracentrifugation and subsequent quantitative analysis byrefractometry or by analytic ultracentrifugal methodology. Apo A1, Apo Band hsCRP can be determined from serum using standard nephelometrytechniques. Lipoprotein (a) can be determined from serum using standardturbidimetric immunoassay techniques. LDL particle number and particlesize can be determined using nuclear magnetic resonance (NMR)spectrometry. Remnants lipoproteins and LDL-phospholipase A2 can bedetermined from EDTA plasma or serum and serum, respectively, usingenzymatic immunoseparation techniques. Oxidized LDL, intercellularadhesion molecule-1 and interleukin-2 levels can be determined fromserum using standard enzyme immunoassay techniques. These techniques aredescribed in detail in standard textbooks, for example TietzFundamentals of Clinical Chemistry, 6th Ed. (Burtis, Ashwood and BorterEds.), WB Saunders Company.

In a related embodiment, the reductions or increases of parameters(a)-(y) above are statistically significant.

In another embodiment, the present invention provides a method of bloodlipid therapy comprising administering to a subject in need thereof 1 toa plurality of dosage units comprising a composition or compositions asdisclosed herein. In another embodiment, the subject being treated has abaseline triglyceride level, prior to treatment with a composition ofthe present invention, greater than or equal to about 150 mg/dl, greaterthan or equal to about 175 mg/dl, greater than or equal to about 250mg/dl, or greater than or equal to about 500 mg/dl, for example about200 mg/dl to about 2000 mg/dl, about 300 to about 1800 mg/dl, or about500 mg/dl to about 1500 mg/dl.

In one embodiment, methods of the present invention comprise measuringbaseline levels of one or more markers set forth in (a)-(y) prior todosing the subject or subject group. In another embodiment, the methodscomprise administering a composition as disclosed herein to the subjectafter baseline levels of one or more markers set forth in (a)-(y) aredetermined, and subsequently taking a second measurement of the one ormore markers as measured at baseline for comparison thereto.

In one embodiment, the present invention provides a method of treatingor preventing primary hypercholesteremia and/or mixed dyslipidemia(Fredrickson Types Ila and IIb) in a subject in need thereof, comprisingadministering to the subject a composition or compositions comprisingEPA and one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein. In arelated embodiment, the present invention provides a method of reducingtriglyceride levels in a subject or subjects when treatment with astatin or niacin extended-release monotherapy is considered inadequate(Frederickson type IV hyperlipidemia). Statin or niacin extended-releasemonotherapy is considered inadequate when, for example, the subject'snon-HDL-C level is not lowered or is not lowered to the degree desired,the subject's LDL-C level is not improved or is not improved to thedegree desired, the subject's HDL-C level is not improved or is notimproved to the degree desired, and/or the subject's triglyceride levelis not improved or is not improved to the degree desired.

In another embodiment, the present invention provides a method oftreating or preventing nonfatal myocardial infarction, comprisingadministering to the subject a composition or compositions comprisingEPA and one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating or preventing risk of recurrent nonfatal myocardial infarctionin a subject with a history of myocardial infarction, comprisingadministering to the subject a composition or compositions comprisingEPA and one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method ofslowing progression of or promoting regression of atheroscleroticdisease in a subject in need thereof, comprising administering to thesubject a composition or compositions comprising EPA and one or moreadditional cardiovascular agents (either as a single dosage unit or asmultiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating obesity in a subject in need thereof, comprising administeringto a subject in need thereof a composition or compositions comprisingEPA and one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating or preventing very high serum triglyceride levels (e.g. TypesIV and V hyperlipidemia) in a subject in need thereof, comprisingadministering to the subject a composition or compositions comprisingEPA and one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method oftreating subjects having very high serum triglyceride levels (e.g.greater than 1000 mg/dl or greater than 2000 mg/dl) and that are at riskof developing pancreatitis, comprising administering to the subject acomposition or compositions comprising EPA and one or more additionalcardiovascular agents (either as a single dosage unit or as multipledosage units) as disclosed herein.

In another embodiment, the present invention provides a method ofpreventing recurrence of stroke, comprising administering to a subjectwith a history of stroke a composition or compositions comprising EPAand one or more additional cardiovascular agents (either as a singledosage unit or as multiple dosage units) as disclosed herein.

In another embodiment, the present invention provides a method ofpreventing onset and/or recurrence of cardiovascular events in a subjectwho has escaped the unstable period after cardiovascular angioplasty,comprising administering to the subject a composition or compositionscomprising EPA and one or more additional cardiovascular agents (eitheras a single dosage unit or as multiple dosage units) as disclosedherein.

In another embodiment, the present invention provides a method ofreducing Apo-B and non-HDL cholesterol levels in a subject group with abaseline LDL-cholesterol level of at least 100 mg/dl, a baselinenon-HDL-cholesterol level of at least 130 mg/dl and a baselinetriglyceride level of at least 200 mg/dl, and reducing the Apo-B and thenon-HDL-cholesterol level of the subject group by administering acomposition or compositions comprising EPA and one or more additionalcardiovascular agents (either as a single dosage unit or as multipledosage units) as disclosed herein to members of the subject group.

In another embodiment, the invention provides a method of reducing Apo-Blevels in a subject group, comprising measuring LDL-cholesterol,non-HDL-cholesterol, and triglyceride levels in subjects, providing asubject group with a baseline LDL-cholesterol level of at least 100mg/dL, a baseline non-HDL-cholesterol level of at least 130 mg/dL, and abaseline triglyceride level of at least 200 mg/dL, and reducing theApo-B levels of the subject group by administering to members of thesubject group a composition or compositions comprising EPA and one ormore additional cardiovascular agents (either as a single dosage unit oras multiple dosage units) as disclosed herein in an amount effective toreduce the Apo-B levels of the subject group in a statisticallysignificant amount as compared to a control treatment, wherein anincrease or statistically significant increase of LDL-cholesterol levelis avoided.

In another embodiment, the invention provides a method of reducing Apo-Blevels in a subject group, comprising providing a subject group with abaseline LDL-cholesterol level of at least 100 mg/dL, a baselinenon-HDL-cholesterol level of at least 130 mg/dL, and a baselinetriglyceride level of at least 200 mg/dL, reducing the Apo-B levels ofthe subject group by administering to members of the subject group a acomposition or compositions comprising EPA and one or more additionalcardiovascular agents (either as a single dosage unit or as multipledosage units) as disclosed herein in an amount effective to reduce theApo-B levels of the subject group in a statistically significant amountas compared to a control treatment, and determining the reduction in theApo-B levels of the subject group.

In one embodiment, a composition of the invention is administered to asubject in an amount sufficient to provide a daily EPA dose of about 1mg to about 10,000 mg, 25 about 5000 mg, about 50 to about 3000 mg,about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, forexample about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050mg, about 1075 mg, about 1100 mg, about 1025 mg, about 1050 mg, about1075 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg,about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg,about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg,about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg,about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450mg, about 2475 mg, or about 2500 mg.

In the various embodiments of the invention described herein, the EPAand optional one or more additional cardiovascular agents can beadministered as a co-formulated single dosage unit, or as individualdosage units. Where the EPA and optional one or more additionalcardiovascular agents are co-administered as separate dosage units, eachdosage unit can be administered to a subject at substantially the sameor substantially different times. In one embodiment, where two or moreindividual dosage units are to be administered daily, each dosage unitcan be administered to the subject within a period of about 24 hours, 18hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour,or 0.5 hours.

In another embodiment, the EPA and one or more optional cardiovascularagents can be administered sequentially. For example, EPA can beadministered to a subject as a sole agent during an EPA loading period.The loading period can be, for example, 1 day, 2 days, 4 days, 6 days, 2weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks or10 weeks. After any such loading period, one or more additionalcardiovascular agents can be initiated together with current EPAadministration or in place of EPA treatment.

In another embodiment, EPA is administered to a subject in the morning,for example from about 4 am to about 10 am, about 5 am to about 9 am, orabout 6 am to about 8 am, and the optional one or more cardiovascularagents are administered to the subject in the afternoon or evening, forexample from about 1 pm to about 11 pm, about 2 pm to about 10 pm, orabout 3 pm to about 9 pm, or vice versa.

In another embodiment, the invention provides the use of EPA and one ormore cardiovascular agents in the manufacture of a medicament fortreatment or prevention of a cardiovascular-related disease such ashypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronaryheart disease, vascular disease, stroke, atherosclerosis, arrhythmia,hypertension, myocardial infarction, and other cardiovascular events. Inone embodiment, the composition contains not more than 10% DHA, if any.In another embodiment, the composition contains substantially no or noDHA.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising EPA and one or more cardiovascular agents for thetreatment and/or prevention of a cardiovascular-related disease, whereinthe composition contains not more than 10% DHA, if any. In a relatedembodiment, the composition contains substantially no DHA or no DHA.

In one embodiment, a subject being treated with a composition or regimenset forth herein is a diabetic or pre-diabetic subject.

In one embodiment, any of the methods disclosed herein are used intreatment or prevention of a subject or subjects that consume atraditional Western diet. In one embodiment, the methods of theinvention include a step of identifying a subject as a Western dietconsumer or prudent diet consumer and then treating the subject if thesubject is deemed to consume a Western diet. The term “Western diet”herein refers generally to a typical diet consisting of, by percentageof total calories, about 45% to about 50% carbohydrate, about 35 toabout 40% fat, and about 10% to about 15% protein. A Western diet mayfurther be characterized by relatively high intakes of red and processedmeats, sweets, refined grains, and desserts, for example where half ormore or 70% or more calories come from these sources.

It is to be understood that a wide range of changes and modifications tothe embodiments described above will be apparent to those skilled in theart and are contemplated. It is, therefore, intended that the foregoingdetailed description be regarded as illustrative rather than limiting,and that it be understood that it is the following claims, including allequivalents, that are intended to define the spirit and scope of theinvention.

It should be understood that various changes and modifications to thepresently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present subjectmatter and without diminishing its intended advantages. It is thereforeintended that such changes and modifications be covered by the appendedclaims.

EXAMPLES

The following non-limiting examples are for illustrative purposes onlyand are not to be construed as limiting the invention in any manner.

Example 1

An experiment was conducted to test EPA, DHA, EPA+DHA with and withoutwith atorvastatin in model membranes enriched with PUFAs and cholesterolat levels that reproduce disease or high CV-risk conditions (i.e.hypercholesterimia). As is shown below, EPA exhibits a potentantioxidant benefit in cholesterol-enriched membranes that was superiorto that observed with DHA. Moreover, the combination of EPA andatorvastating provided even further antioxidant benefit by comparison toEPA alone.

EPA and DHA were tested individually at a fixed concentration of 10.0 uMor in combination at 5.65 μM and 4.35 μM (EPA and DHA, respectively),which is a mole ratio of 1.3:1. Separate and combined effects of theseagents on lipid peroxide (LOOH) formation were examined atcholesterol-to-phospholipid (C/P) mole ratios of 0.5:1, 1.0:1 and 1.5:1.Levels of lipid hydroperoxides were also measured for EPA, DPH andEPA/DPH in cholesterol-enriched membrane prepared in the absence andpresence of atorvastatin.

1,2-Dilinoleoyl-3-sn-phosphatidylcholine (DLPC) was obtained from AvantiPolar Lipids (Alabaster, Ala.) and stored in chloroform (25 mg/ml) at−80° C. until use. Cholesterol obtained and stored in chloroform (10mg/ml) at −20° C. CHOD-iodide color reagent (stock) was preparedaccording to a procedure modified from El-Saadani et al. (ElSaadani M,Esterbauer H, El-Sayed M, Goher M, Nassar A Y, Jurgens G. Aspectrophotometric assay for lipid peroxides in serum lipoproteins usingcommercially available reagent. J Lipid Res 1989; 30:627-30) consistedof 0.2 M K₂HPO₄, 0.12 M KI, 0.15 mM NaN₃, 10 1 . . . EM ammoniummolybdate, and 0.1 g/L benzalkonium chloride. Prior to experimental use,the CHOD reagent was activated by adding 24 μMethylenediaminetetraacetic acid (EDTA), 20 μM butylated hydroxytoluene(BHT), and 0.2% Triton X-100. Atorvastatin was prepared in ethanol justprior to experimental use and added together with component lipidscontaining fixed amounts of EPA, DPH or EPA/DPH at equimolar levels. Thecompounds and lipids were added in combination during membrane samplepreparation to ensure full incorporation into the lipid bilayers.

Membrane samples consisting of DLPC±cholesterol, withcholesterol-to-phospholipid (C/P) mole ratios ranging from 0.5 to 1.5,were prepared as follows. Component lipids (in chloroform) weretransferred to 13×100 mm test tubes and shell-dried under a steadystream of nitrogen gas while vortex mixing. The lipid was co-dried withEPA, DPH or EPA/DPH prepared in the absence or presence of theatorvastatin at equimolar levels.

Residual solvent was removed by drying for a minimum of 3 h undervacuum. After desiccation, each membrane sample was resuspended indiffraction buffer (0.5 mM HEPES, 154 mM NaCl, pH 7.3) to yield a finalphospholipid concentration of 1.0 mg/ml. Multilamellar vesicles (MLV)were formed by vortex mixing for 3 minutes at ambient temperature.Bangham A D, Standish M M, Watkins J C. Diffusion of univalent ionsacross the lamellae of swollen phospholipids. J Mol Biol 1965;13:238-52. Immediately after initial MLV preparation, aliquots of eachmembrane sample will be taken for baseline (0 h) peroxidation analyses.

All lipid membrane samples were subjected to time-dependent autoxidationby incubating at 37° C. in an uncovered, shaking water bath. Smallaliquots of each sample were removed at 24 h intervals and combined with1.0 ml of active CHOD-iodide color reagent. To ensure spectrophotometricreadings within the optimum absorbance range, sample volumes taken formeasurement of lipid peroxide formation were adjusted for length ofperoxidation and range between 100 and 10 μl. Test samples wereimmediately covered with foil and incubated at room temperature for >4 hin the absence of light. Absorbances were measured against a CHOD blankat 365 nm using a Beckman DU-640 spectrophotometer.

The CHOD colorimetric assay is based on the oxidation of iodide (I⁻) bylipid hydroperoxides (LOOH) and proceeds according to the followingreaction scheme:LOOH+2H⁺+3I⁻→LOH+H₂O+I₃ ⁻

The quantity of triiodide anion (I₃ ⁻) liberated in this reaction isdirectly proportional to the amount of lipid hydroperoxides present inthe membrane sample. The molar absorptivity value (ε) of I₃ ⁻ is2.46×10⁴ M⁻¹ cm⁻¹ at 365 nm.

Results are shown in FIGS. 1-4.

We claim:
 1. A method of treating or preventing a cardiovascular diseasein a subject on statin therapy having type 2 diabetes, the methodcomprising administering to the subject a pharmaceutical compositioncomprising about 4 g of eicosapentaenoic acid ethyl ester per day,wherein the cardiovascular disease is myocardial infarction, stroke, orboth.
 2. The method of claim 1, wherein the statin therapy is stablestatin therapy.
 3. The method of claim 2, wherein the statin is selectedfrom lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin,fluvastatin, atorvastatin and simvastatin.
 4. The method of claim 1,wherein the subject does not exhibit an increase in low densitylipoprotein-C (LDL-C) levels after administration of the pharmaceuticalcomposition as compared to baseline or placebo control.
 5. The method ofclaim 1, wherein the subject has fasting baseline triglyceride levelsbetween about 150 mg/dl to about 500 mg/dl.
 6. The method of claim 1,wherein the subject exhibits a reduction in triglycerides levels by atleast 30% after administration of the pharmaceutical composition.
 7. Themethod of claim 1, wherein the subject exhibits a reduction intriglycerides levels by at least 40% after administration of thepharmaceutical composition.
 8. The method of claim 1, wherein thesubject exhibits a reduction in triglycerides levels by at least 50%after administration of the pharmaceutical composition.
 9. The method ofclaim 1, wherein the 4 g of eicosapentaenoic acid ethyl ester isadministered to the subject in 4 capsules.
 10. The method of claim 9,wherein the capsules each comprises about 1 g of eicosapentaenoic acidethyl ester.
 11. The method of claim 1, wherein the pharmaceuticalcomposition is administered to the subject in 1 to 4 dosage units perday.
 12. The method of claim 1, wherein the pharmaceutical compositioncomprises at least about 90%, by weight of all fatty acids present,eicosapentaenoic acid ethyl ester.
 13. The method of claim 1, whereinthe subject has atherosclerosis.